Stimuli-responsive nano-assemblies for remotely controlled drug delivery

Journal Pre-proof Stimuli-responsive nano-assemblies for remotely controlled drug delivery

Fangyuan Li, Yu Qin, Jiyoung Lee, Hongwei Liao, Nan Wang, Thomas P. Davis, Ruirui Qiao, Daishun Ling PII:

S0168-3659(20)30209-1

DOI:

https://doi.org/10.1016/j.jconrel.2020.03.051

Reference:

COREL 10253

To appear in:

Journal of Controlled Release

Received date:

20 December 2019

Revised date:

19 March 2020

Accepted date:

31 March 2020

Please cite this article as: F. Li, Y. Qin, J. Lee, et al., Stimuli-responsive nano-assemblies for remotely controlled drug delivery, Journal of Controlled Release (2019), https://doi.org/10.1016/j.jconrel.2020.03.051

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

© 2019 Published by Elsevier.

Journal Pre-proof Stimuli-responsive nano-assemblies for remotely controlled drug delivery Fangyuan Lia,b,1 , Yu Qinc,1 , Jiyoung Leea,1 , Hongwei Liaoa, Nan Wanga, Thomas P. Davisc,d, Ruirui Qiaoc,d,*, and Daishun Linga,b,e* a

Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University,

Hangzhou 310058, China b

Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences,

Zhejiang University, Hangzhou 310058, China ARC Centre of Excellence in Convergent Bio-Nano Science and Technology,

f

c

oo

Australian Institute for Bioengineering and Nanotechnology, The University of

d

pr

Queensland, Brisbane, Queensland 4072, Australia

ARC Centre of Excellence in Convergent Bio-Nano Science and Technology,

e

Pr

Parkville, Victoria 3052, Australia

e-

Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade,

Key Laboratory of Biomedical Engineering of the Ministry of Education, College of

al

Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou 310058, China

These authors contributed equally to this work.

rn

1

Jo u

* Corresponding authors.

E-mail addresses: [email protected] (D. Ling), [email protected] (R. Qiao)

ABSTRACT

Stimuli- responsive nano-assemblies are emerging as promising drug delivery systems (DDSs) with spatial and temporal tenability, which can undergo structural transition for controlled drug release upon excitation by either exogenous or endogenous stimuli. Particularly, exogenous stimuli-responsive nano-assemblies based remotely controlled DDSs, have received much attention due to their accuracy and reliability realized by tunable exogenous triggers such as light, magnetic field, or temperature. In this review, we will briefly introduce the current state-of-the-art technologies of 1

Journal Pre-proof nano-assembly synthesis and summarize the recent advances in remotely controlled nano-assembly-based

DDSs

activated

by

different

exogenous

stimuli

or

endogenous/exogenous dual-stimuli. Furthermore, the pioneering progress in bio-cleanable stimuli-responsive nano-assemblies that holds great relevance to clinical translation will be described. Finally, we will conclude with our perspectives on current issues and future development of this field. The objective of this review is to outline current advances of nano-assemblies as remotely controlled DDSs, in hopes of

f

accelerating the future development of intelligent nanomedicines.

oo

Keywords: Nano-assemblies; Stimuli- responsiveness; Controlled drug delivery;

pr

Bio-cleanable nano-systems.

e-

1. Introduction

Pr

By virtue of constant effort and innovation, nanomedicine and nanobiotechnology have advanced rapidly, which undeniably prompts the development of diverse nanomaterials as a novel form of drug delivery systems (DDSs). In recent years,

al

nano-assemblies are fabricated to circumvent the limitations of conventional small

rn

molecular drugs such as undesired aggregation, high plasma protein binding rate, poor

Jo u

solubility and bioavailability, rapid metabolism, etc. [1-6]. For example, pegylated liposomal doxorubicin (PLD), also known as Doxil/Caelyx, is the first FDA-approved nanomedicine for a variety of cancers, including ovarian cancer [7]. The encapsulation of doxorubicin (DOX) into liposomes extended the circulation duration and improved the drug stability during blood circulation, without premature drug leakage. Moreover, PLD evidently accumulated in tumor site with high vascular permeability, which greatly reduced the undesirable side effects of DOX, such as cardiac

toxicity [8].

Furthermore,

by

incorporating

targeting

components,

nano-assemblies can exert site-specific therapeutic function, thereby reducing potential side effects caused by the poor selectivity of the conventional drugs [9-11].

2

Journal Pre-proof Lately, stimuli- responsive nano-assemblies attracted tremendous attention, as they allow a remotely controlled multistage activation, and have raised the concept of developing effective DDSs through compartmentalization and selective activation approaches. The utilization of remote stimuli, such as alternating magnetic field (AMF), near- infrared (NIR), or ultrasound radiations, can trigger the release of drugs in a controlled manner. In addition, responsive moieties, such as stimuli-sensitive polymers, photosensitizers, photothermal agents, magnetic nanoparticles, gas bubbles,

f

etc. are key components of exogenous stimuli-responsive nano-assemblies that can

oo

undergo energy transfer, structural rearrangements and/or chemical cleavage in

pr

response to various external stimuli [12]. The combination of the properties of each component leads to synergized nano-assemblies performance. Particularly, such an

e-

“on-demand” drug delivery strategy has enticed a lot of attention by researchers due

Pr

to its ability in attaining dosage-, spatial-, and temporal- controllability, in response to endogenous or exogenous stimuli [13, 14]. Among the variety of options, the most

al

commonly used endogenous stimuli include pH variation, redox gradie nt, enzymes, etc. [15], whereas exogenous stimuli are represented by light, magnetic field (MF),

rn

ultrasound, electric field, temperature, etc. [16, 17].

Jo u

Compared to the endogenous stimuli in the biological environment, the responsiveness of the nano-assembly to exogenous stimuli can sense remotely controlled action at specific spatial and temporal points. Once externally applied to the targeted tissues, exogenous stimuli can be easily controlled after the administration of specific nano-assembly with the loaded drugs. This ensures that the rationally-designed nano-assemblies can be activated at the right time and place. Alternatively, endogenous stimuli enriched in the disease microenvironment, such as pH variation, redox gradient, and specific enzymes, enables autonomous drug delivery by the activation of the responsive components in the nano-assembly. The administered drug in the form of endogenous stimuli-responsive nano-assemblies could enrich at the target sites due to their high selectivity [18], thereby exerting 3

Journal Pre-proof reduced side effects and a higher therapeutic index [19]. The construction of stimuli-responsive nano-assemblies generally involves the combination of both organic (i.e., polymers, small molecules, biomacromolecules) and inorganic (i.e., superparamagnetic iron oxide nanoparticles (SPIONs), gold nanoparticles (AuNPs), upconversion nanoparticles (UCNPs)) in one entity [20]. Both of which are indispensable components that form the foundation of the responsive and tunable nature of the controlled DDS (Fig. 1).

f

In this review, we will introduce the current state-of-the-art technologies of

oo

nano-assemblies construction, and then summarize the pioneering studies of remotely

pr

controlled nano-assembly-based DDSs. Endogenous stimuli (pH [21-23], redox [24, 25], enzyme [26-29], ROS [30-32], and hypoxia [33-37]) responsive nano-assemblies

e-

will not be discussed here, which can be found in other co mprehensive reviews as

Pr

listed. Instead, this review mainly focuses on the construction and in vivo bioapplications of nano-assemblies that can be triggered by exogenous or

al

exogenous/endogenous stimuli for the purpose of controlled drug release. In addition,

rn

the endogenous and exogenous dual-stimuli- responsive nano-assembly systems will be described. Finally, we will discuss the bio-cleanable stimuli-responsive

DDSs.

Jo u

nano-assemblies that holds great relevance to the biosafety and clinical translation of

4

pr

oo

f

Journal Pre-proof

Fig. 1. Schematic illustration of the nano-assemblies based drug delivery system and

e-

available stimuli. With the assistance of various external stimuli, the well-designed

Pr

stimuli-responsive nano-assemblies from different assembly moieties such as polymeric NPs, mesoporous silica nanoparticles (MSNs), IONPs, Au NPs, and

al

UCNPs, could be activated. Consequently, it can achieve guided delivery, targeting, controlled drug release, and treatments. After fulfilling the biological function,

rn

triggered disassembly of the remotely controllable nano-system leads to the swift

Jo u

clearance of nanocarrier components, which helps to effectively minimize the potential systemic toxicity. Consequently, remotely controllable nano-assemblies are emerging as a powerful platform for DDS due to their high therapeutic efficiency and reduced side effects.

2. Construction of stimuli-responsive nano-assemblies Nano-assembly provides a reliable and practical way to build up DDSs with improved in vivo performance. To synthesize a stimuli-responsive nano-assembly, various nanomaterials and/or small molecules are modified, functionalized, and assembled via different mechanisms to eventually form the nano-assembly. Among multiple

strategies,

typical

approaches

in

constructing

stimuli-responsive 5

Journal Pre-proof nano-assemblies are based on small molecular assemblies, polymeric assemblies, liposome assemblies, inorganic assemblies, nanocrystal assemblies and metal organic frameworks (MOFs). 2.1. Small molecular assemblies Small molecular assemblies are nanoparticles (NPs) assembled by organic compounds with low molecular weight (< 900 Da) [38]. The small molecules constitute the majority of the clinically approved drugs. However, most small

oo

f

molecule drugs are hydrophobic in nature, resulting in poor water solubility and low bioavailability [39]. Therefore, controlled assembly methods are introduced to solve

pr

these problems by assembling the small molecular drugs into water-soluble

e-

nano- formulations [40]. Moreover, stimuli-responsive moieties can be incorporated for the localized collapse of the assembly and controlled drug release. The

Pr

functionalized and stimuli-responsive small molecule assemblies can incorporate distinct properties, which significantly improve the solubility and bioavailability of the

Jo u

rn

al

drugs for enhanced therapeutic efficiency (Fig. 2).

Fig. 2. Schematic illustration of different types of small molecular assembly. (a) Assembly of the hydrophobic drugs into a nano-assembly after conjugation to hydrophilic peptide via a degradable linker. (b) Nanostructured prodrug assembled by engineered amphiphilic prodrug with hydrophilic promoieties.

6

Journal Pre-proof The small molecular assembly is well driven by electrostatics, π−π stacking, and hydrophobic interaction. For example, Guo et al. [41] constructed a carrier-free nano-DDS (ICG@UA/PTX NPs) (Fig. 3). The system consists of hydrophobic anti-cancer drugs including ursolic acid (UA) and paclitaxel (PTX), and a n amphipathic tissue-penetrating agent, indocyanine green (ICG), which were self-assembled via electrostatic, π−π stacking and hydrophobic interactions. The electrostatics occurs specifically between the charged particles, whereas π−π stacking

f

and hydrophobic interactions occur when aromatic π systems bind with one another

oo

face to face, which involves a combination of dispersion and dipole- induced dipole

pr

interactions. During this process, the amphipathic ICG served as a scaffold which is vital in stabilizing the nanostructure. As a result, the nano-assembly displayed

e-

increased water solubility and circulation time compared to small molecular

Pr

counterparts, which significantly enhanced the therapeutic efficacy. Although this strategy does not require additional modifications, it is difficult to extend to the

al

majority of small molecules, since not all drugs used are in the hydrophilic and hydrophobic setting. Ultimately, the unique chemical structures in this scenario

rn

cannot meet the functional varieties intended for different biomedical applications.

Jo u

Consequently, additional moieties, typically hydrophilic peptides, are conjugated to endow the small molecular drugs with amphiphilic properties for assembling.

7

Journal Pre-proof Fig. 3. Illustration of the self-assembly of carrier- free small molecules. (a) Electrostatic, hydrophobic and π–π stacking driven assembly of the small molecules. (b)Amplified AMF image of the ICG@UA/PTX NPs. The size (c) and (d) zeta of ICG@UA/PTX NPs over 8 days in RPMI, DMEM, FBS, PBS, and aqueous solution. Reprinted with permission from the American Chemical Society [41]. Copyright 2017. For therapeutic applications, peptides with excellent solubility and high affinity for

f

specific biological receptors, are used as a targeted delivery vector to improve

oo

bioavailability and pharmacokinetics of the drugs [42]. They are widely used as

pr

promoieties for the conversion of drugs into prodrugs, which then can assemble into NPs. The choice of peptides affects both the assembly of the conjugate and the

e-

characteristic of the nano-assembly surface directly [43]. In general, the intermediate

Pr

peptide structure determines the morphology of the final nano-assembly. The β-sheet- forming peptides bring one-dimensional (1D) fibrous structures while other

al

intermediate structures would lead to vesicles or micelles [44]. Furthermore, peptide-based epitopes and other moieties could be used to impart additional

rn

functions such as targeting [45]. Furthermore, the use of appropriate linkers is

Jo u

imperative to achieve the optimal releasing effect of the drugs. Currently, there is a variety of bio-responsive linkers, which can be enzyme cleavable, acid-sensitive, reducible, etc. [46]. For instance, MacKay et al. [47] employed a pH-labile linker to conjugate elastin- like polypeptides to DOX, which could self- assemble into chimeric polypeptide nano-assemblies with a hydrophobic drug core surrounded by a hydrophilic peptide corona. This pH-responsive linker could be broken at the acidic tumor region, triggering the disassembly- induced localized drug release for enhanced anti-tumor effects. Likewise, Wang and coworkers utilized the enzyme cleavable peptide linker Pro-Leu-Gly- Val-Arg-Gly (PLGVRG) to conjugate a targeting ligand Arg-Gly-Asp (RGD) to the functional molecule purpurin 18 (P18). The resultant P18-PLGVRGRGD could be severed by gelatinase enriched at the tumor 8

Journal Pre-proof microenvironment, followed by self-assembly of the released P18-PLG to form nanofibers. Such an assembly induced retention (AIR) effect that promoted the accumulation of nanofibers at the tumor sites, ensuring a robust therapeutic efficacy and an enhanced PA signal [48]. The flexible linkers are used to bridge the hydrophobic drugs and the hydrophilic peptides, forming the amphiphilic prodrugs that can assemble into nanoarchitectures (Fig. 2a) [46]. Even though peptide-drug conjugates exhibit the advantages in many aspects over the individual hydrophobic

f

drugs, they are prone to premature release of the drugs and degradation during

oo

circulation, leading to off-target effects or reduced bioavailability. Similar to other

pr

small molecular prodrugs, they are also confronted by hepatic elimination and exceedingly fast renal clearance [49]. In contrast, assembling the amphiphilic

e-

peptide-drug conjugates or prodrugs into larger nanostructures provides better

Pr

protection against non-specific attacks and longer circulation time (Fig. 2b) [50]. 2.2. Polymeric assemblies

al

Polymeric assemblies are NPs assembled by macromolecular polymers including

rn

homopolymers and copolymers [51]. They differ from small molecular assemblies in that their building blocks have much larger molecular mass and thus many unique

Jo u

physiochemical properties. It is also easier to endow the polymeric assemblies with more utilities by exploiting the abundant functional groups the polymers can provide. In addition, unlike small molecular assemblies that can only deliver a very narrow range of drugs/prodrugs, polymeric assemblies are much more flexible and can carry various therapeutic agents such as peptides, proteins, and nucleic acids. The alteration in polymer properties, including the radius of gyration, will promote an extension in circulation duration together with decreased unintended early excretion of the drugs [52]. In addition, polymeric structures with reversible stimuli-responsive properties possess on-off switching ability, thereby achieving controlled release of the drugs [53]. Depending on the hydrophilic/hydrophobic ratio of the polymer and the process of

9

Journal Pre-proof polymeric assembly formation, various structures can be obtained, including

e-

pr

oo

f

polymersomes (bilayer), polymeric micelles (monolayer), and hydrogels [54].

Pr

Fig. 4. Schematic illustration of the construction of polymeric assemblies via (a) hydrophobic interactions and (b) polymerization.

al

In aqueous solution, amphiphilic block copolymers tend to self-assemble into

rn

polymeric micelles or polymersomes due to the hydrophobic interactions of

Jo u

hydrophobic segments (Fig. 4a). Hydrophobic drugs can be incorporated into the hydrophobic block of copolymers, thereby being introduced into the core of polymeric micelles, or into the hydrophobic bilayer of polymersomes [55]. For example, Wei et al. [56] fabricated a four-arm block copolymer which composes of a hydrophobic

PMMA

arm

and

an

average

poly(N-isopropylacrylamide) (PNIPAAm) arms

(Fig.

of 5).

three

hydrophilic

These star-shaped

amphiphilic copolymer micelles can self- assemble into micelles in aqueous media with PNIPAAm block as the hydrophilic shell and PMMA block as the hydrophobic core. Prednisone acetate was successfully incorporated into the hydrophobic core of micelles. When the temperature was raised above 40 °C, these thermosensitive micelles experienced soluble–insoluble change, and significantly accelerated the release of prednisone acetate. In comparison with micelles, polymersomes are capable 10

Journal Pre-proof of co-delivering hydrophilic and hydrophobic cargos owing to their bilayer structure,

Pr

e-

pr

oo

f

demonstrating an excellent versatility [57].

al

Fig. 5. Hydrophobic interactions mediated Self-assembly of a star block copolymer.

rn

(a) Schematic illustration of the assembling process of the star block copolymer. (b)

Jo u

TEM images of the self- assembled, thermosensitive micelles. (c) Optical absorbance of the self- assembled thermosensitive micelles upon temperature changes. (d) Fluorescence intensity of pyrene in the emission spectra with increasing concentration of the star block copolymers. Reprinted with permission from Elsevier [56]. Copyright 2007. The monomers are self-assembled into hydrogel via free radical polymerization with the aid of an initiator and cross- linkers. This assembly pattern is an efficient approach to control the size of gels [58], and endow the polymers with a three-dimensional network structure (Fig. 4b). These hydrogels have the ability to ferry both hydrophobic and hydrophilic payloads owing to their unique structure. In addition, stimuli-responsive hydrogels can undergo phase transformation or volume change in response to either external or endogenous triggers, and exhibit specific functions [59]. 11

Journal Pre-proof For example, Han et al. developed a polydopamine-NPs loaded NIR-responsive poly(N-isopropylacrylamide)

(PNIPAM)-based

hydrogel

(PDA-NPs/PNIPAM

Hydrogel) by in situ free radical polymerization of N-isopropylacrylamide in the polydopamine-NPs suspension. Polydopamine-NPs with high tissue adhesiveness are excellent photothermal agents that provided hydrogel with high cell affinity and NIR responsiveness. Meanwhile, PNIPAM Hydrogel with good thermosensitivity showed structure rearrangement in response to temperature rise. As a result, the

f

PDA-NPs/PNIPAM hydrogel afforded NIR-activatable drug release. Upon NIR laser

oo

irradiation, the release of dexamethasone (model drug) from hydrogel was switched

pr

on, which could be reversibly switched off by removing the laser power. Thereby, a pulsatile drug release profile was observed d uring the on-off cycles of the laser. In

e-

addition, PDA-NPs/PNIPAM hydrogel showed enhanced tissue adhesiveness

Pr

compared with pristine hydrogel and achieved excellent cell affinity as well as NIR-assisted healing performance. The in vivo full- skin defect experiments further

al

demonstrated that the hydrogel could accelerate wound healing, indicating their

Jo u

rn

potential applications for tissue engineering (Fig. 6) [60].

12

Jo u

rn

al

Pr

e-

pr

oo

f

Journal Pre-proof

Fig. 6. Free radical polymerization mediated assembly of NIR-responsive hydrogels. (a) Schematic illustration of the fabrication process of the PDA-NPs/PNIPAM hydrogel. (i) The construction of PDA-NPs by oxidative self-polymerization, (ii) PDA-NPs/PNIPAM Hydrogel was prepared by in situ free radical polymerizations of N-isopropylacrylamide in the PDA-NPs suspension. (b) Photographs of the bilayer hydrogel (left: PDA-NPs/PNIPAM layer, right: pure PNIPAM layer) before and after NIR irradiation. The blue circle shows water was squeezed out from contracted hydrogel due to the NIR irradiation- induced heat diffusion of the PNIPAM layer. (c) 13

Journal Pre-proof Temperature curves of PDA-NPs/PNIPAM hydrogels upon irradiation-cooling cycles (irradiation duration: 1 min/test). (d) Instantaneous dexamethasone release from PDA-NPs/PNIPAM hydrogels with different PDA-NPs contents under NIR irradiation. Reprinted with permission from the American Chemical Society [60]. Copyright 2016. 2.3. Liposome assemblies Liposomes have a physical structure similar to polymersomes and can also be

oo

f

chemically functionalized with a stimuli-responsive moiety to finely tune their properties [57]. Liposomes are typically composed of naturally occurring and/or

pr

synthetic amphipathic phospholipids, such as phosphatidylcholine, phosphatidylserine,

e-

phosphatidylethanolamine, and phosphatidylglycerol, which can self-assemble into lipid bilayer spheres in the aqueous medium due to the hydrophobic interactions

Pr

between the hydrophobic acyl chains and the surrounding aqueous solutions (Fig.7)

Jo u

rn

al

[61].

Fig. 7. Schematic illustration of the construction of liposome assemblies via hydrophobic interactions.

The bilayer structure of liposomes enables them to load the hydrophobic drugs in the lipid membrane interior and hydrophilic drugs in the aqueous lumen. Moreover, liposomes are inherently thermosensitive, whose permeability can be greatly increased around the membrane melting temperature (Tm) depending on the lipid composition [62]. Based on this property, photothermal agents or magnetic NPs have been incorporated to trigger the release of the drugs from liposomes upon light or AMF, respectively. For example, Amstad et al. developed PEGylated liposomes hosting IONPs in their membranes. These liposomes were colloidally stable at body 14

Journal Pre-proof temperature. When exposed to AMF, the localized heating of embedded IONPs led to a lipid melting phase transition, which changed the permeability of the lipid membrane. Since the liposome structure was retained upon AMF treatment, the cargo could be repeatedly released from liposomes at bulk temperatures without the risk of burst [63]. In addition to thermosensitivity, liposomes can also be formulated with pH-, redox-, enzyme-, or light-sensitivity by using various phospholipids such as pH-sensitive [64],

pH

and

redox-sensitive

f

1,2-dioleoyl-sn- glycero-3-phosphoethanolamine

oo

2-[2-(2-carboxylcyclohexylformamido)-3,12-dioxy-1-(1H- imidazolyl-4)-7,8-dithio-4,

pr

11 diazapentadecylamide]- glutaric acid ditetradecanol-diester (HH-SS-E2C14) [65], secretory

phospholipase

(DPPC)

[66],

and

1,2-bis(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine

Pr

photo-polymerizable

e-

(1,2-dipalmitoyl-sn-glycero-3-phosphocholine)

A2 -hydrolyzable

(DC8,9 PC ) [67]. For example, Liu et al. developed a novel redox-activatable liposome,

al

which was self-assembled by phospholipid-porphyrin conjugates via disulfide bonds. The IDO inhibitor (NLG-8189) was encapsulated into the lumen of the liposomes to

rn

realize the triggered release of NLG-8189 in response to the high concentration of

Jo u

glutathione (GSH) in tumors. The liposomes showed structure-driven self-quenching of pyropheophorbide-a (PPa) signals due to the homofluorescence resonance energy transfer. After incubation with reductive media (10 mM GSH containing 0.1% Triton X-100), the liposomes exhibited exponential activation of the fluorescence signal (>100-fold) after the cleavage of the disulfide bonds. Upon laser irradiation, porphyrin-based PDT promoted immunogenic cell death of tumor cells. Meanwhile, PDT combined with the release of IDO inhibitors further augmented the systemic antitumor immune response [68]. 2.4. Inorganic assemblies Inorganic nanoparticles, which mainly include mesoporous silica, quantum dots (QDs), gold, silver, magnetic nanoparticles, exhibits unique size-dependent, and 15

Journal Pre-proof tunable magnetic, electrical, optical, and catalytic features [69, 70], and have drawn immense attention in various biomedical applications. Their assembly often confers collective properties that are different from individual NPs and the corresponding bulk materials (Fig. 8). The coupling interactions among NPs, such as dipole-dipole attractions, electrostatic interactions, hydrogen bonding, and hydrophobic/hydrophilic interactions, can generate an intriguing variety of physiochemical properties [71-75]. Even though there are diverse strategies to address the drawbacks in inorganic NP

f

synthesis, the development of controlled assembly of NPs to attain intended

oo

complexity and functionality still remains a great challenge. The ideal strategy to

pr

circumvent this challenge involves assembly based on the surface of the inorganic NP

Jo u

rn

al

Pr

e-

core.

Fig. 8. Schematic illustration of various inorganic assemblies. (a) Illustration of inorganic core assembly with functional moieties. (b) Illustration of MSN-inorganic NP fabrication procedure. (c) Illustration of drug encapsulated hollow mesoporous silica assembly.

These inorganic cores have several distinguishing characteristics. Firstly, excellent flexibility in surface modification, which guarantees well-defined assembly with 16

Journal Pre-proof multiple functions. Normally, the surface of the NPs is modified by various moieties for structural and functional purposes, such as polyethylene glycol for colloidal stability, and sensors or fluorescent dyes for imaging (Fig. 8a). Incorporation of versatile surface functionalities can be achieved by non-covalent adsorption or covalent binding of surface ligands and moieties, which in many cases entails linkers responsive to a specific stimulus. Overall, these structural or functiona l modules in one single structure of inorganic assembly collectively promote high colloidal

f

stability, biocompatibility, and targeting ability, while enabling multiple functions

oo

including imaging, sensing, therapies, and controlled release of the drugs [76, 77].

pr

Secondly, controllable synthesis. The surface-to-volume ratio, size, and shape of inorganic NPs can be readily adjusted according to different biomedical purposes. For

e-

instance, the size of IONPs can be fine-tuned with a variety of surfactants in the

Pr

synthesizing process. For the typical thermal decomposition method, ultrafine IONPs of 3 nm could be produced in the presence of iron-oleate complex, oleyl alcohol, oleic

al

acid, and diphenyl ether. While IONPs with size of 2.2 nm were produced without the addition of oleic acid [78]. Lastly, the unique features of inorganic NPs bring about

photodynamic

properties,

whereas

iron

oxide

magnetic

Jo u

photothermal and

rn

additional functions [79]. For example, the remarkable plasmonic Au NPs can inherit

nanoparticles (MNPs), typically, SPIONs can be used as a high-performance contrast agent for magnetic resonance imaging (MRI) [80]. Inorganic nanoparticle assemblies often serve as responsive drug nanocarriers, delivering drugs to the target sites and releasing them in a controlled manner upon external stimuli. Drugs can be conjugated on the surface of the NPs via electrostatic adsorption or covalent bonding, or loaded inside inorganic NPs such as MSNs [81]. The pores of MSNs are tunable in size and volumes, which can be capped by various materials via chemical modification or non-covalent coating, to realize the controlled release of the drugs. Besides, the surface of inorganic NPs can be decorated with other NPs. For example, Wu et al. [82] developed a uniform mesoporous silica nanoparticle 17

Journal Pre-proof decorated with ultra-small ceria nanocrystals (MSN-Ceria) (Fig. 8b). The surface of MSN was functionalized with an amine group for enhanced immobilization of ceria nanocrystals with outstanding ROS scavenging capacity. Furthermore, hollow mesoporous silica (HMSN), which has a tunable hollow core, is capable of encapsulating the drugs and can be sealed by other NPs including Au NPs, Ag NPs, QDs and MNPs with responsive linkage (Fig. 8c). Therefore, the nano-assemblies are not only capable of loading drugs, but can also minimize the premature drug release,

oo

f

ensuring a high therapeutic index [83]. 2.5. Nanocrystals assemblies

pr

As an alternative building moiety for the construction of assemblies, inorganic

e-

nanocrystals are increasingly appealing to researchers due to their inherently attractive physicochemical characterizations and functionalities which can be used for the

Pr

diagnosis and/or treatment. For instance, Au NPs with surface plasmon resonance properties have effective light- harvested performance, whereby they are widely used

al

in biological imaging and light-stimulated controlled delivery of drugs [84]. UCNPs

rn

with unique optical properties can also be used for nidus detection or light-related

Jo u

targeted release of the drugs [85]. On top of that, the inherited magnetism of IONPs could also be used for the targeted drug delivery or magnetic separation with the direction of the MF.

18

e-

pr

oo

f

Journal Pre-proof

Pr

Fig. 9. Schematic illustration for the controlled fabrication of nanocrystal assemblies

dipole-dipole interaction.

al

through (a) hydrophobic interaction, (b) hydrogen-bonding interaction, and (c)

rn

Since the assembly of nanocrystals has distinct optical, magnetic, mechanical or

Jo u

other collective performance that is different from their individual counterparts, controlled assembling of inorganic nanocrystals brings in a new idea to realize precise drug delivery or bioimaging for improved therapeutic outcomes. In the consideration that most inorganic nanocrystals are synthesized in organic solutions, hydrophobic interaction mediated assembly plays a vital role in the assembling process. Amphiphilic copolymers are usually served as a platform to encapsulate or graft the nanocrystals with oily capping with its hydrophobic segments, and to guarantee the colloidal stability with its hydrophilic segments stretching in the aqueous solution (Fig. 9a) [86]. For example, Nie et al. co-assembled hydrophobic IONPs and amphiphilic Au NPs with free amphiphilic copolymers and further constructed hybrid magneto-plasmonic janus vesicles (JVs) through the hydrophobic interactions between the assembly moieties [87]. The improved magnetism of the nano-assembly 19

Journal Pre-proof assured the magnetic field-mediated targeting behavior. In addition, the controlled release of the drugs could further be achieved under NIR irradiation through photothermal- induced structural collapse, where the release rate could be finely increased by the introduced MF via magnetism- guided concentrating of the vehicles for enhanced photothermal heating (Fig. 10). Similarly, another research reported by Zhang et al. demonstrated a photothermal-responsive nanocomposite assembled by ultrafine Au NPs and DOX, with comb- like amphipathic copolymers as the templates

f

via the hydrophilic/hydrophobic interactions [88]. Under laser irradiation, the

Jo u

rn

al

Pr

e-

pr

oo

Au-based nano-assembly fragmented and triggered the on-demand release of DOX.

Fig. 10. Hydrophobic interaction mediated assembly for the construction of hybrid magneto-plasmonic JVs. (a) Self-assembly of hydrophobic IONPs, amphiphilic Au NPs, and free amphiphilic copolymers into hybrid magneto-plasmonic JVs with different shapes. EDS mapping of hybrid JVs of spherical (b) and hemispherical (c) shapes. (d) Phase- like diagram of hybrid JVs with different shapes. (Key: circle: 20

Journal Pre-proof spherical JVs, square: spherical homogenous vesicles, triangle: hemispherical JVs) Reprinted with permission from Wiley-VCH [87]. Copyright 2016. Apart from the hydrophobic interaction mediated assembly, the fabrication of nanocrystal assemblies can also be achieved through hydrogen-bonding mediated interaction (Fig. 9b). Due to the specific base pairing complementary of DNA molecules, inorganic nanocrystals anchored with single-strand DNA (ssDNA) allows the self-assembly with the assistance of complementary sequence- modified

f

nanocrystals through the hydrogen bonding [89]. For instance, Tan and co-workers

oo

developed a size-controllable light-responsive nanocrystal assembly via DNA

pr

hybridization. In this strategy, small Au NPs loaded with DOX (termed nanodrugs) were initially modified with ssDNA, which were further tethered to the

e-

complementary sequence-anchored Au NRs through hydrogen-bonding interaction.

Pr

Under NIR irradiation, the light harvested by Au NRs was converted to heat and caused denaturation of DNA double strands, triggering the disassembling process and

al

controlled nanodrugs release [90].

Moreover, the dipole-dipole interaction also facilitates the assembly process o

rn

f nanocrystals (Fig. 9c). Klajn et al. demonstrated that the dipole-dipole interac

Jo u

tion between the azobenzene groups could be utilized for the construction of li ght-responsive nano-assemblies [91]. They selectively modified thiolated 4-(dime thylamino)azobenzene (ligand 1) and a parent azobenzene (ligand 2) onto the s urface of Au NPs of 2.5 nm and 5.5 nm in size, separately. After being expos ed in blue light, the trans to cis-transition of 1 selectively initiated the assembl y process of Au NPs of 2.5 nm. It is noted that, such assembling/disassembling behavior is reversible. The disassembly of 2.5 nm Au NPs could be achieved through the irradiation by UV light, while the UV light could simultaneously trigger the self-assembly of 5.5 nm Au NPs through trans to cis-transition. Alternatively, such disassembling behavior could also be achieved by heating, demonstrating a possibility of multiple activations. 21

Journal Pre-proof 2.6. Metal organic frameworks (MOFs) MOFs are a class of porous hybrid materials with infinite tunability, which are also known as coordination networks. They are assembled by the coordination of inorganic metal ions with the organic, polydentate bridging ligands mostly under mild conditions [92-94]. The moderate coordination bond energies of the MOF materials can modulate the reversibly self-correcting kinetic properties of the MOF structure, which promotes flexibility in the geometry, size, and functionality of the products

f

without changing the underlying topology. As a result, they possess architecturally

oo

robust crystalline structures, high surface-to-volume ratio with uniform and tunable

pr

pore structures, as well as confined nanopore microenvironments [95, 96]. Moreover, the physicochemical properties functionalize the MOFs according to the application

e-

purposes as they can offer virtually vast combinations of metals and ligands. Hence,

Pr

bulk phase MOFs are ideal candidates for diverse applications, such as catalysis of organic reactions [97-99], light harvesting [100] and sensing [101, 102]. Furthermore,

al

due to high surface areas with large pore sizes, MOFs have been studied for the

rn

applications in drug delivery and controlled drug release [103-105]. MOFs can be further scaled down to form nanoscale metal organic frameworks (NMOFs), which

Jo u

can serve as efficient drug delivery vehicles with high loading capacity [106-108]. Moreover, since they are constructed by the self-assembly of the biomedically relevant building blocks, metal ions, and organic binding ligands, some hydrophobic, amphiphilic and hydrophilic drugs can be loaded via direct incorporation during the assembly of NMOF or post-synthesis loading (Fig 11). Particularly, post-synthetic covalent attachment of the therapeutic agent is an efficient approac h, which can realize controlled drug release through the decomposition of NMOF.

22

al

Pr

e-

pr

oo

f

Journal Pre-proof

rn

Fig 11. Schematic illustration of the relevant biomedical agents incorporation to NMOFs via different strategies. (a) Direct incorporation of relevant biomedical metal ligands.

(b)

Post-synthesis

Jo u

bridging

encapsulation

through

non-covalent

interactions.(c) Post-synthesis incorporation through covalent loading. For instance, Taylor-Pashow et al. synthesized Fe(III)-carboxylate NMOFs of the MIL-101 structure [109]. The bridging ligand (terephthalic acid) was partially replaced with 2-amino terephthalic acid to incorporate amine groups into the framework. Through covalent modification, the organic fluorophore and the anticancer drugs were successfully loaded without any changes in the MIL-101 structure. The controlled drug release was realized upon the degradation of NMOFs. Through the utilization of this strategy, Taylor-Pashow et al. successfully created a new prodrug and demonstrated an effective in vitro anticancer therapy against HT-29 human colon adenocarcinoma cells. The explicit control of MOFs assembly is likely 23

Journal Pre-proof to drive this field into new synthetic chemistry domains which could grant access to more sophisticated and promising materials [110, 111]. 3. Exogenous stimuli-responsive nano-assemblies Exogenous triggers, exemplified by light, magnetic field, ultrasound, and electric field, have gained increasing interest as controlled DDSs. With external triggers as the remote control, smart nano-assemblies allow the manipulation of the dosage, location,

f

and timing of the release of entrapped agents, providing divinable regulation of

oo

nano-assembly-based DDS.

pr

3.1. Light stimuli-driven

As a particularly appealing external stimulus, light has been widely adopted in

e-

various fields, including photoinduced polymerization [112], photocatalysis [113],

Pr

optical fluorescence imaging [114], environmental cleaning and disinfection [115], etc. Among various external stimuli strategies, light ranging from deep blue to the

al

NIR exhibits a distinctive strength due to its range of unique photon energy falling

rn

into a suitable range which allows safe interactions with organic molecules. The regulatory safety and non- invasive character of light made it an ideal candidate for

Jo u

medical applications [116]. Ultraviolet (UV) and visible (Vis) light (short-wavelength light) have been applied to crack the photolabile groups and excite photosensitive agents. However, the low tissue penetration depth of these short-wavelength lights limits their applications in the biomedical field [117]. In addition, the harmful photodamage on healthy tissues caused by UV irradiation, such as UV-induced DNA damage and carcinogenic capacity of skin cells, has not been solved [118, 119]. Unlike UV and Vis light, NIR light with wavelengths ranging from 650 to 2100 nm can significantly enhance light penetration depth due to its lowered scattering and absorption by soft tissues, blood, and water [120]. Moreover, the ability to spatiotemporally restrict photochemical reactions with minimal photodamaging makes NIR more preferable [121]. These features make NIR-sensitive nano-systems 24

Journal Pre-proof hopeful for on-demand drug delivery without affecting superficial tissues. Currently, a large number of nanomaterials, such as semiconductor nanomaterials (eg. copper sulfides, bismuth sulfide), Au-based nanomaterials (eg. Au NPs, Au nanorods (NRs)), carbon nanomaterials (e.g. GOs, carbon nanodots), UCNPs, etc, have been used for the construction of NIR-responsive delivery systems [122, 123]. These materials exhibit a maximal optical absorbance in the NIR region, contributing to

the construction of NIR-activated

nano-assemblies [124].

Apart

from

f

nano- materials, several dye molecules (e.g. ICG, and IR780) [123, 125] and

oo

conjugated polyelectrolytes [126], which can generate heat energy by absorbing NIR

pr

light and consequently excite their electrons, are also excellent NIR-responsive agents. To activate the site-specific release, these NIR-responsive agents convert light energy

e-

to heat and/or ROS and indirectly disrupt the nano-assemblies [127, 128]. For

Pr

example, Li and co-workers fabricated the phototriggered, clustered vesicles with the oxygen-generating ability and tissue penetrability for PDT against the hypoxic tumor.

al

H2 O 2 and chlorin e6 (Ce6)/cypate conjugated poly(amidoamine) dendrimer (CC-PAMAM) were encapsulated into ROS-responsive triblock copolymer. Upon

rn

805 nm irradiation, the H2 O2 was decomposed into O 2 due to the light-triggered

Jo u

thermal effect. Followed by 660 nm light irradiation, the generation of ROS by photosensitizers further triggered the cleavage of thioketal moiety, inducing the destabilization of vesicles and the subsequent release of photoactive CC-PAMAM [129]. Generally, the construction of NIR-responsive nano-assemblies is the integration of photolabile agents, and/or thermosensitive moieties, amphiphilic polymer, and other bioactive molecules [130-132], with the introduction of excitation light, these nano-assemblies would be triggered to release the encapsulated therapeutics for targeted treatment. For instance, Yu et al. [133] developed a croconaine dye (CR, as a NIR-sensitive agent) and camptothecin (CPT, as a chemotherapeutical agent) linked trimeric prodrug (CR-(SS-CPT)2 ), and encapsulated CR-(SS-CPT)2 into folate (FA) modified lipid-polymer NPs (termed as FA-CSC-NPs) 25

Journal Pre-proof for imaging- guided tumor therapy. Upon laser irradiation, hyperthermia (HT) generated by the active CR group accelerates the cleavage of a disulfide (-SS-) bond, leading to the controlled release of CPT. This FA modified lipid-polymer NPs function as a good accommodation with a protectable coat for CR-(SS-CPT)2 and significantly improved tumor targeting in combination with therapeutic efficacy (Fig.

12.

Lipid-polymer

coated

NIR-sensitive

prodrug

(FA-CSC-NPs)

for

rn

Fig.

al

Pr

e-

pr

oo

f

12).

photoacoustic imaging- guided chemo-photothermal synergistic therapy. (a) Schematic

Jo u

illustration of formulation and application of FA-CSC-NPs for light-triggered imaging- guided chemo-thermal therapy. (CSC: croconaine-(SS-camptothecin)2 ; PLGA:

poly

DSPE-PEG-FA:

lactide-co-glycolide; 1,

SPC:

soybean

phosphati-dylcholine;

2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[folate

(polyethylene glycol)-200).

(b) The release profile of camptothecin

from

FA-CSC-NPs. The NIR-triggered release was conducted by irradiating samples with a NIR laser (1 W/cm2 ) for 5 min, each arrow indicates the time points. (c) The curves show the tumor growth of various groups after the indicated treatments. Reprinted with permission from the Royal Society of Chemistry. [133]. Copyright 2018. Among the existing NIR-responsive nanomaterials for photo- mediated delivery 26

Journal Pre-proof systems, UCNPs have been used as a photosensitizer in a wide range of bio-applications, including drug delivery, photodynamic therapy (PDT), photothermal therapy (PTT), bioimaging, and bio-detections. In striking contrast with other photolabile agents that are sensitive to light of short wavelengths, UCNPs are specifically responsive to NIR that features deep tissue penetration with less light scattering [134]. A UCNP generally consists of a crystalline host (as a matrix to control position) and a dopant (as luminescent centers). The dopant is usually trivalent

f

lanthanide ions, such as La, Nd, Eu, Ho, Er, Sm, and Tm [135, 136]. These inorganic

oo

icons have many special optical properties including anti-photobleaching and low

pr

background fluorescence, that turn UCNPs to robust light-triggered nano-delivery components.

e-

Multiple studies had attempted to modify UCNPs with functional groups to

Pr

improve the responsive property. Currently, UCNPs-based nano-assemblies designs have been classified into two typical patterns: mesoporous silica shells-shielded

al

UCNPs [137] and an amphiphilic polymer- grafted layer for the functionalization of UCNPs [138]. For example, Tian et al. [139] fabricated a carboxy-terminated

rn

silica-coated NaErF4 : 10% Yb@NaYF4 : 40% Yb@NaNdF4 : 10% Yb@NaGdF4 : 20%

Jo u

Yb UCNP (UCNP@SiO 2 -COOH). This UCNPs hybrid can convert 808 nm excitation to 655 nm up conversion luminescence (UCL) emission, thereby enabling a clear visualization of the deep-tissue tumors. These carboxy-terminated mesoporous silica shells enable UCNP to be modified with various targeting molecules, which improved its tumor-homing efficacy (Fig. 13).

27

e-

pr

oo

f

Journal Pre-proof

Pr

Fig. 13. Mesoporous silica shells-shielded UCNPs for ultrasensitive in vivo imaging and treatment of colorectal tumor: (a) Synthesis of a core- multishell-type UCNPs. (b)

al

Schematic illustration of the biodistributions, clearance pathways, and tumor-targeting capacities of the UCNP@SiO 2 -COOH and three bioconjugates. Reprinted with

rn

permission from Nature Publishing Group [139] . Copyright 2010.

Jo u

Nevertheless, in some cases, the mesoporous silica shells-shielded method is not capable of releasing the hydrophobic therapeutics in the pores of mesoporous silica due to multiple unsolved obstacles. Moreover, the hydrophilic agents are prone to leakage when the pores of mesoporous silica are uncapped. Hence, the amphiphilic polymer is alternatively used as a conjugation layer for the functionalization of UCNPs and the encapsulation of poor water-soluble agents. For instance, our group has recently [140] developed a pH-responsive polymeric ligands‐ assisted assembly of UCNPs (PPNs) which comprises a UCNP core, pH-sensitive copolymer, and Pluronic F68 (F68) surfactant (Fig. 14a). Upon 980 nm irradiation, UCNPs core could transfer the laser of 980 nm wavelength to the emission of about 660 nm (Fig. 14b), which corresponds to one of the absorbance peaks of Ce6 and activate the 28

Journal Pre-proof photoactivity of Ce6. As shown in Fig. 14c, PPNs + Pork + NIR group have demonstrated significantly higher antitumor efficacy than red light‐ irradiated PPNs + Pork group, indicating that NIR controlled PPNs are capable to be used in PDT of deep‐ seated tumors. Additionally, UCNP mediated NIR-controllable PDT (PPNs + NIR group) significantly inhibited the tumor growth compared with the red light-activated group (PPNs + NIR), exhibiting the attractive properties of the UCNP‐ mediated therapeutic selectivity. This strategy gives an insight to the

f

researchers regarding extremely beneficial UCNPs-based activation for selective PDT

Jo u

rn

al

Pr

e-

pr

oo

of deep tumors.

29

Jo u

rn

al

Pr

e-

pr

oo

f

Journal Pre-proof

Fig. 14. Polymer encapsulated UCNPs for NIR-triggered photoactivity of Ce6, and PDT of deep tumors: (a) Molecular design and assembly of pH-responsive ligand‐ assisted UCNPs (PPNs). (b) The application of PPNs for PDT of deep tissue. (c) Cell viability of A549 cells treated by PPNs with 980 nm laser irradiation at either pH 6.5 or 7.4. (The concentration of Ce6 in PIPNs or PPNs are represented by the indicated concentrations). The values represent the mean ± standard deviation (SD). (n = 6 per group). *P < 0.05 in comparison to other groups according to multiple t-tests. (d) The changes in relative tumor volume (Vd /V0 ) in various groups after the indicated 30

Journal Pre-proof treatments. “+Pork” represents the tumors of those involving a group covered with 7‐ mm‐ thick pork tissues. Reprinted with permission from Wiley-VCH [140]. Copyright 2018. UCNPs

represent

one

of

the

inorganic

NP-based

photo-responsive

agents/nano-carrier, whereas other significant inorganic nanocomplexes including Au NPs [141], various nanodots [142], TiO 2 nanotube [143], CuS [144], carbon-based nanomaterials [145], and some hybrid nanostructures, also exhibit highly efficient

f

light-sensitive photothermal efficiency. Au NPs can concurrently be served as both

oo

the photosensitive unit and cargo delivery carriers. This “all in one” nanoplatform can

pr

respond to NIR irradiation, and subsequently activate functional cargos encapsulated within Au NPs or on the surface of NPs for the remotely controlled delivery. For

e-

example, a recent study reported by Yang et al. [146] demonstrated the application of

Pr

the porous Au@Pt NPs (DOX/Au@Pt-cRGD) for reactive oxygen scavenging and remotely controlled drug delivery. In this study, DOX exhibited excellent interaction

al

with the metal surface and was efficiently absorbed in the pores of Au@Pt NPs. The release of absorbed DOX from DOX/Au@Pt-cRGD was accelerated by NIR

rn

irradiation-induced temperature rise, achieving exceptional chemo-photothermal

Jo u

therapy. In light of the high photoconversion efficiency, minimum photo-toxicity compared with UV irradiation, and the superior tissue penetrability, NIR-activating inorganic photolabile structures is evoking extensive research interest. Another example reported by Yang et al. [147] was the developed tellurium (Te) nanodots based nanostructures for effective photothermal conversion and reactive oxygen species (ROS) generation. Te nanodots possess effective photothermal conversion upon laser irradiation and perfect resistance to photobleaching. Besides, it is reported that the Te-containing nanocomplexes are more effective than conventional photosensitizers or photothermal agents, which provided the opportunity of using elemental Te nanodots as controllable light-sensitive nano-assemblies [148, 149]. 3.2. Alternating magnetic field stimuli-driven 31

Journal Pre-proof MF stimulus has the advantages of non- invasive and multifunctional that can direct magnetic nanomaterials respond with a high degree of spatiotemporal accuracy. In addition, MF has another advantage of being able to penetrate into the deep tissues, which remedies the limitation of optical or acoustic penetration depth [150]. As widely used materials with regard to MF, magnetic nanomaterials are recently drawing more interests for their biomedical applications [151], such as HT therapy [152], controllable drug delivery [153], biosensors [154], and medical diagnosis

f

[155].

oo

Unlike photolabile moieties, which have a wide range of varieties, the types of the magnetic core are relatively narrow. Only iron oxide (including metal-doped iron

pr

oxides (MFe2 O4 ), wüstite (FeO), magnetite (Fe3 O4 ), maghemite (γ-Fe2 O3 )) [156-158],

e-

Ni [159], and Co [160] have been reported as magnetic cores for biomedical

Pr

application. Since these naked metallic compounds are chemically highly active and prone to be oxidized in air, they can be easily demagnetized and aggregated. This

al

problem arose the researchers’ attention to the synthesis of magnetic NPs. In recent years, chemists and materials scientists have made rapid progress in designing and

rn

synthesizing the stable, size-controllable, and monodisperse magnetic nanoparticles

Jo u

(MNPs) [161, 162]. Typically, Fe3 O4 and γ-Fe2 O3 are commonly used in medical research due to their preferable biocompatibility. Moreover, some MNPs, such as magnetic ferrite nanoparticles (MFNPs), can induce HT under the AMF, which brings a breakthrough in cancer treatment. For example, Ferjaoui and co-worker [163] developed a DOX loaded thermos-responsive core/shell magnetic nanoparticles (abbreviated as Fe3 - δO4 @P(MEO 2 MA60OEGMA40 )), which were composed of Fe3 - δO4 NPs (as the magnetic core), DOX (as the therapeutic), 2-(2-methoxy)ethyl methacrylate (MEO 2 MA) and oligo(ethylene glycol)methacrylate (OEGMA) moieties (as the thermo-responsive copolymer shell). Under low AC magnetic field, the IONPs generated heat due to their Brownian and/or Neel's spin relaxations. The temperature continued rising and quickly reached the required magnetic hyperthermia (MH) 32

Journal Pre-proof temperature (i.e., 41- 45 °C). Then, the release of the drug occurred and 100% of DOX was released within 52 h. With the increased selectivity, improved cytotoxicity, and the controlled release of the drugs, the described “smart” superparamagnetic nanocarriers were demonstrated to be promising for multimodal cancer therapy. Among various MNPs, IONPs are popular for biomedical uses owing to their excellent biocompatibility and magnetic responsibility. Several IONPs have been evaluated in the preclinical and clinical trials, and some of them were approved by the

f

FDA. For instance, Ferumoxytol (Feraheme® (USA) Rienso® (EU)) was approved as

oo

an iron supplement by FDA in 2009, and it is feasible for off- label clinical use [164].

pr

In addition, a growing number of researches have shown the potential of Ferumoxytol as imaging agents [165]. Another representative commercialized IONP is

e-

Ferucarbotran (Resovist® (USA, Japan, EU), Cliavist® (France)), an organ-specific

Pr

MRI contrast agent, which is still available on the markets of Europe, Japan, Australia and China [166]. However, Resovist® is no longer manufactured since 2009, and it is

al

gradually replaced by Primovist (Gd-DTPA). Hopefully, with the rapid advances in IONP-based materials and their great promise shown in in vivo applications, we may

rn

witness more translational successes in the future. Herein, we highlight a few recent

Jo u

examples of novel nano-systems for AMF modulated drug delivery. IONPs-mediated MH is expected to be a new breakthrough in thermal therapy due to their relative safety to adjacent healthy tissues. For example, Tabatabaei et al. [167] exploited a new strategy to enhance the permeability of the blood-brain-barrier (BBB) by using the magnetic heating technique. In this system, the thermal energy generated by MNPs with eight different coatings was precisely regulated by a low radiofrequency (RF) field, and the suitable heat improved BBB drug delivery without perturbing other brain cells. In the last few years, tremendous efforts have been made for the AMF triggered remotely controlled DDS. Magnetic thermal agents, such as Fe3 O4 and γ-Fe2 O3 , have particularly been extensively used in MH or MRI. In these cases, assembling provides 33

Journal Pre-proof a practical and reproducible approach for functional moieties to enhance their application properties. Most of these researches introduced SPION into a thermosensitive polymeric shell (such as dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) [168], poly(ethylene glycol)-b-(N-isopropylacrylamide-co-p-NAPMA) [169], azo- functionalized polyethylene glycol [170], P(DEGMA-co-HPMA-co-PEGMA) copolymers [171], etc.) or mesoporous silica compartment through physical interaction. For example, assembly of MNPs within mesoporous silica compartment

f

and/or biocompatible polymers provides an ideal way to improve the performance and

oo

stability of MNPs. Importantly, the surface coating of MNPs with biocompatible

pr

ligands can effectively alleviate the agglomeration of MNPs in aqueous media, grant them with high colloidal stability and improved biocompatiblity, and provide a

e-

platform for coupling functional groups including antibodies, biomarkers, and

Pr

peptides. In fact, surface modification with biocompatible ligands lays the foundation for constructing multifunctional and smart drug delivery vehicles [172].

al

Alternatively, Bai et al. [173] made full use of polymeric noncapsule to develop a triple- modal fluorescence/MR/SPECT imaging system. Oleic acid coated SPION and

rn

ICG was encapsulated in a PEGylated PLGA polymeric shell. A radio- isotope

Jo u

chelator (diethylene triamine pentaacetic acid (DTPA)) was covalently conjugated to the PEGylated PLGA polymer shell for further binding with

111

In as SPECT/CT

imaging probe. Fluorescence signals of ICG in tumor sites were significantly enhanced after a permanent magnet (0.515 T) was attached at the tumor site for 1 h. Meanwhile, ex vivo organ images and quantification demonstrated that the fluorescence intensity of the tumor site in the magnet-treated group almost tripled when compared to the signal from the no- magnet treated group. Moreover, this multifunctional platform was capable of in vivo fluorescence/MR/SPECT imaging and can overcome the limitations of monomorphic imaging. To enhance magnetic properties, metal-doped oxides for responsive drug delivery are developed in recent years and different approaches have been exploited to 34

Journal Pre-proof synthesize MFe2 O4 (where M can be Fe, Mn, Ni, Zn, Co, etc.) [174]. Recently, Chen et al [175] synthesized 11.4 nm MnFe2 O4 @CoFe2 O4 NPs, which showed a higher saturated magnetization than that of Fe3 O 4 MNPs. Moreover, the MnFe2 O 4 @CoFe2 O4 NPs were encapsulated into the mesoporous shell and could generate heat under AMF in a more effective way. 4,4′-azobis(4-cyanovaleric acid) (ACVA), which can be irreversibly cleaved by heat and ultrasound, was further anchored on the core@shell NPs to control release of the drugs in response to heat generation. As shown in Fig.

f

15, the burst release of β-cyclodextrin (β-CD) and 1-adamantylamine (AMA)

oo

occurred during the exposure of AMF. Meanwhile, the amount of released cargo

pr

could be adjusted by the controlling the duration of exposure to AMF. This study demonstrated that the MnFe2 O4 @CoFe2 O4 core, ACVA, and mesoporous shell-based

e-

core@shell NPs are capable to achieve the dosage, temporal, and spatial control of

Jo u

rn

al

Pr

therapeutics delivery through the AMF exposure.

35

Journal Pre-proof Fig. 15. MnFe2 O4 @CoFe2 O4 NPs for spatial, temporal, and dose control of drug delivery using non- invasive magnetic stimulation: (a) Schematic illustration of the function of Mag@MSNs- for AMF-triggered dose controllable cargo release. (b- g) The fluorescein release profile form Mag@MSNs after magnetic actuation under AMF for (b) 1, (c) 2, (d) 3, (e) 5, and (f) 10 min, respectively. (g) The release efficiency of fluorescein at a plateau and the solution temperature after the various time periods of triggers under AMF (N = 3). Reprinted with permission from the

oo

f

American Chemical Society [175]. Copyright 2019. 3.3. Ultrasound stimuli-driven

pr

In addition to light and MF stimuli, other forms of external stimulus such as

e-

ultrasound (US) has been gradually developed to control drug delivery in recent years. Alternative US-controlled nano-assembly composed of US-responsive agents and

Pr

various delivery carriers (including polymersomes, micelles, liposomes, gel, mesoporous silicon, etc.) has been frequently investigated. When the US-responsive

al

nano-assemblies are subjected to a certain ultrasound wave, the nano-assemblies can

rn

be activated through US- mediated cavitation, acoustic fluid streaming, pressure

Jo u

variation, or local HT [176]. These physical effects can destroy the stability of nanocarriers and lead to the release of the drugs. Additionally, the acoustic force can further improve the local permeability or absorptivity of target tissues, and help the active molecules to pass through the tight tissues. For example, Chen et al. [177] developed a US-triggering DDS based on the combination of GMBL (des-octanoyl ghrelin-conjugated microbubbles (GMB) loaded with TGFβ1 inhibitors (LY364947)) NPs and FPD (folate-conjugated polymersomal DOX) (FPD+GMBL/US). The strong T2 signal intensity (SI; 0.45, 2 h) at the site of the brain tumor of a rat model treated with GMBL/US have confirmed the enhanced SPIONs accumulation in tumors of the GMBL/US group in comparison to other groups. Upon focused US sonication, the rupture of GMB was capable of disturbing the blood-brain barrier/blood-tumor barrier (BBB/BTB), and subsequently enhanced vascular permeability of GMBL. Meanwhile, 36

Journal Pre-proof LY364947 was released from GMBL, decreasing the pericyte coverage of the endothelium in the neovasculature of the targeted brain tumor sites ( Fig. 16). Consequently, FPD + GMBL/US treatment led to a high DOX concentration in the brain tumor of the rat, resulting in significantly elevated apoptosis of the tumor cells as revealed by TUNEL analysis. Thus, this strategy provided an alternative for brain

Pr

e-

pr

oo

f

drug delivery without irresolvable damage to BBB.

Fig. 16. Ultrasound sonication-triggered DDS based on microbubbles for blood-brain

al

barrier/blood-tumor barrier (BBB/BTB) brain tumor treatment: (a) Drawings of the

rn

structure of des-octanoyl ghrelin-conjugated microbubbles-carrying TGFβ1 inhibitor LY364947 (GMBL) and folate-conjugated polymersomal doxorubicin (FPD), and the

Jo u

combination of GMBL, FPD, ultrasound for crossing the blood-brain barrier/blood tumor barrier (BBB/BTB) and overcoming the brain tumors. (b) TUNEL analysis of brain tumor parts attained from the tumor-bearing mice treated with various formulations at the same dose of Dox on day 20 after the implantation of C6 glioma. Green: Marked apoptosis cells by FITC. (c) T2 -weighted images of the mouse brain tumor in vivo demonstrate the distribution of designed SPIONs. At an acoustic power of 2.86 W, the brain tumor of the mouse was sonicated with US, MB/US, GMB/US, and GMBL/US, respectively. Reprinted with permission from Elsevier [177]. Copyright 2015.

37

Journal Pre-proof Microbubbles or gas-generators are popular choices in designing US-sensitive vehicles for remotely controllable drug delivery.

A typical O 2 -absorbent,

perfluorocarbon (PFC), has been explored as a contrast enhancement agent as well as an oxygen transporter for biomedical applications. For example, Song et al. [178] developed a US triggered oxygen delivery system, in which PFC nanodroplets could absorb oxygen from the lung and rapidly release oxygen upon US stimulation at the tumor site. As an oxygen transport and US-sensitive agent, the utilization of

f

nano-PFC is a promising strategy to circumvent the hypoxia-associated resistance in

oo

cancer treatment. Moreover, microbubbles can be a good gatekeeper for US

pr

controllable release of the drugs. For example, Lin et al. [179] developed an emulsion liposome (eLiposomes) based on DPPC liposome, a perfluoropentane (PFC5 )

e-

nanodroplet, and DOX. It was demonstrated that the size of PFC5 and DOX loaded

Pr

eLiposomes increased with US insolation, and the release of DOX increased with duration and power of external US treatment. Additionally, high- intensity US waves

al

can also lead to the oscillating movement of US-sensitive materials and subsequently transfer to thermal energy [180]. In this case, the US triggered drug release converts

rn

to thermal-activated drug release, which was mentioned previously in the light

Jo u

stimuli-triggered DDS section [181]. 3.4. Electric field (EF) stimuli-driven The electric field is also a physical stimulus which has a similar mode of action as the MF. The superposition of van der Waals forces of attraction and the repulsive electrostatic force of attraction determines the interaction between the particles in a medium [182]. The attractive force will prevail when there is a huge particle-particle distance, while the repulsive force dominates when the particles are in close proximity. Simultaneously, NPs go beyond the repulsive energy barrier which results in aggregation. Therefore, external electric field induction of the dipole interaction in NPs could be utilized for controlling nanoparticle assembly. The external electric field establishment results in a robust anisotropic dipole interaction that could be 38

Journal Pre-proof individually controlled by external field adjustments [183]. When the molecular thermal motion is overcome by strong interaction, intended nano-assembly can be obtained in a particular electric condition. Hence, the electric signals can promote stringent

control

over

drug

release

by

nano-assembly,

which

acts

on

electro-responsive materials, such as conductive polymers that are widely used in constructing responsive nano-assemblies. They are promising matrix that can rapidly change under the EF activated convection force, thereby affecting the absorption and

behavior of conducting polymer (poly(3,4-ethylenedioxythiophene)

oo

releasing

f

desorption of loaded drugs. For example, Boehler et al. [184] investigated the

pr

(PEDOT)) coated dexamethasone (PEDOT/Dex) by applying a cyclic voltammetry (CV) signal in the three-electrode system (Fig. 17). After 12 weeks of electrodes

e-

implantation, a low degree of inflammation was found in electrodes site, and more

Pr

neurons appeared in the area exposed to electrodes side. This phenomenon demonstrated that the electrodes-triggered release of the drugs could effectively

al

improve the therapeutic effect of PEDOT/Dex. In this regard, in vivo electrochemical measurements were performed and Dex was released once a week through the applied

rn

cyclic voltammetry (CV) signals in three-electrode systems implanted in the

Jo u

conscious animals, which demonstrated a low risk of causing inflammation, assuring the long-term safety of the neural interfaces. Besides, this PEDOT release system effectively avoided the systemic side effects by ensuring highly localized drug delivery to the electrode site and allowing efficient temporal control over release. Consequently, drug dosage can be scheduled to specific time points over a long period of time, or even be programmed as a feedback to a surveillance parameter such as inflammation status [185]. Other promising conducting polymers including doped polypyrrole, N-methyl pyrrole, and polyaniline are also excellent candidates as EF-controlled nano-assemblies [186]. However, electro-responsive vehicles have not been used in clinical practice. Thus, more efforts are needed in the future to explore the potential of EF-triggering nano-assemblies for biomedical applications. 39

Jo u

rn

al

Pr

e-

pr

oo

f

Journal Pre-proof

Fig. 17. Electric field responsive nano-assembly for efficient drug delivery with low inflammation for chronic scar tissue formation treatment: (a) The microscope image of the polyimide neural probe having electrode sites coated with 4 PEDOT/Dex. The active (specialized) and the passive probe (control) are inserted and fixed in the skull. The active probe is connected to the recording/stimulation equipment by the connector fixed on the head of the mice. (b) CSC of the PEDOT/Dex coated probe before and after 12 weeks of implantation in vivo. Error bars denote standard deviation (n = 4). (c) The inset depicts a pathway where the intensity of the GFAP 40

Journal Pre-proof fluorescence was measured and averaged out with the usage of 50 μm wide ROI. (d) The distance of neurons for various coating materials on polyimide probes. Data displays the average over n = 30, the standard deviation in (d) is denoted by the error bars. (e) ED1-staining for microglia activity displays a lower intensity for PEDOT/Dex probes in comparison to the PEDOT/PSS controls. Reprinted with permission from Elsevier [184]. Copyright 2017.

addition

to

single

exogenous

stimulus-responsive

oo

In

f

4. Exogenous/endogenous dual stimuli-responsive nano-assemblies nano-assemblies,

nano-assemblies that synergistically respond to both exogenous and endogenous

pr

stimuli are also trending. This exogenous/endogenous dual-responsive delivery

4.1. Light/pH stimuli-driven

Pr

cargo delivery and release [187].

e-

system represents a new concept in DDSs, which can provide enhanced control of

al

Thus far, the nano-assemblies-based DDS that combines both light and pH stimuli

rn

as external and endogenous triggers for the controlled release of drugs had been one of the most favorable approaches among different types of dual-responsive DDSs. For

Jo u

example, Li et al. [188] developed a NIR/pH dual-responsive bismuth nanoraspberries (Bi-BSA NRs) for imaging-guided cancer combination therapy. The Bi2 O3 nanosphere was synthesized initially, which served as the template for the synthesis of Bi NRs by a facile reduction method. Since the naked Bi NRs are prone to aggregation in the presence of salt, the Bi NRs were decorated with bovine serum albumin (BSA), which significantly enhanced the dispersibility and stability of Bi-BSA NRs. The highly porous nature and large specific surface area of Bi- BSA NRs results in a high DOX loading capacity (∼69 wt %). Bi-BSA@DOX NRs exhibited an excellent photothermal heating effect upon laser irradiation, which could accelerate DOX release from NRs due to the thermal vibration. Moreover, the acidic environment further potentiated DOX release by sensitizing preferential drug release 41

Journal Pre-proof at targeted sites. Henceforth, Bi-BSA NRs are promising probes for infrared thermal (IRT)/X-ray computed tomography (CT) and photoacoustic (PA) imaging due to its high X-ray attenuation coefficient, strong NIR absorption, and efficient photothermal

Jo u

rn

al

Pr

e-

pr

oo

f

conversion properties (Fig. 18).

Fig. 18. BSA modified bismuth nanoraspberries (Bi- BSA NRs) for NIR/pH triggered drug release, multimodal imaging, and cancer combination therapy: (a) Schematic illustration of the biomedical applications of the dual-stimuli responsive. (b) Representative TEM image of the Bi NRs. (c) The DOX loading capacity of Bi-BSA@DOX NRs. (d) The release profiles of DOX from Bi- BSA@DOX NRs at pH = 7.4 and 5.0 in the presence/absence of laser irradiation (1.0 W·cm–2 ). (e) In vivo CT images of HeLa tumor-bearing mice after administration of the Bi-BSA NRs. The tumor region is marked by the yellow dotted line circle. (f) In vivo IRT images of tumor-bearing mice after various treatment. (g) Tumor growth profiles upon various

42

Journal Pre-proof treatments. Reprinted with permission from the American Chemical Society [188]. Copyright 2018. Huang et al. [189], encapsulated DOX into pH low insertion peptide (pHLIP)- and thermoresponsive

poly(di(ethylene

methacrylate-co-oligo(ethylene

glycol)

glycol)

methyl

methyl ether

ether

methacrylate)

polymer-conjugated gold nanocages (DOX@pPGNCs), which possessed high sensitivity to the acidic microenvironment and temperature > 41.6°C. In this strategy,

f

the acidic condition- induced conformational transformation of pHLIP enhanced the

oo

cellular internalization of DOX@pPGNCs. Meanwhile, the thermoresponsive

pr

polymer shrank upon laser irradiation, which subsequently exposed the pores of gold nanocages (GNCs), resulting in a burst intracellular DOX release. Hence, this pH-NIR

e-

dual responsive DDS presented potent antitumor effects in the adriamycin-resistant

Pr

tumor model. Researchers have demonstrated that the engineered nano-assemblies, with the combination of light and pH as a stimulus, provide the possibility for the

al

delivery of various cargos. However, this approach had encountered various challenges in biomedical applications [190]. For example, as a widely used clinical

rn

anti-tumor drug, Platinum (Pt)-based drugs were found to induce severe toxic side

Jo u

effects to normal tissues [191, 192]. In order to exert the merits of Pt-based drugs to enhance anti-tumor efficiency, and avoid the undesired side effects, Xu et al. recently designed a charge-convertible Pt (IV) prodrugs loaded NaYF4 :Yb,Tm UCNP, with a polymeric coating (termed UCNPs-Pt(IV)@PEG-PAH-DMMA). The pH-triggered charge-shifting of the anionic polymer could result in the release of UCNPs-Pt (IV). Simultaneously, NIR-activated UV light emission from UCNPs, together with the reductive environment in tumor cells, efficiently activated the switching from Pt (IV) prodrugs to highly cytotoxic Pt (II), thus achieving NIR improved chemotherapy. Moreover, the Yb3+ ions doped UCNP can be used as CT contrast agent, combined with its inherent UCL capabilities, a platform of CT/UCL dual imaging-guided chemotherapy can be achieved [193]. 43

Journal Pre-proof 4.2. Light/hypoxia stimuli-driven Recent studies have found that the cooperative enhancement interactions between light and hypoxia stimuli could undoubtedly improve the sensitivity of a nano-assembly. For instance, Qian et al. developed a novel light-activated hypoxia‐ responsive

nano-assemblies

(designated

DOX/CP‐NI

NPs)

based

on

2‐

nitroimidazole‐grafted multifunctional conjugated polymers (CP‐NI), polyvinyl

oo

f

alcohol (PVA), and DOX. Among which, the multifunctional conjugated polymers (CP) synthesized by alternating copolymerization of fluorene, dithiophene‐

pr

benzotriazole moiety (a sensitizer for Vis/NIR light‐activated ROS generation), and

e-

the dithiophene‐thienopyrazine monomers through the Suzuki cross‐coupling reaction.

Pr

The hydrophobic 2‐nitroimidazole of CP‐NI can shift to hydrophilic components in response to a hypoxic environment. As shown in Fig. 19, the light- induced ROS

This

rn

prompting DOX release.

al

generation lowered the oxygen levels, leading to the dissociation of DOX/CP‐NI NPs, innovative design enhanced the traditional

Jo u

photodynamic therapeutic efficacy, and the light-activated oxygen consumption further exacerbates the hypoxic microenvironment of the tumor, inducing a burst release of DOX and achieving synergistic antitumor activity [194].

44

pr

oo

f

Journal Pre-proof

Fig. 19. Light-activated hypoxia-responsive nano-assemblies (DOX/CP‐NI NPs) for

e-

photodynamic enhanced chemotherapy of cancer: (a) Synthesis and disassembly

Pr

process of DOX/CP‐NI NPs. (b) Schematic illustration of DOX/CP‐NI NPs for efficient PDT integrated with a controlled DOX‐release modality. (c) Fluorescence

al

images of the HeLa tumor‐bearing mice after intravenous injection of DOX/CP‐NI NPs. The red arrows point out the sites of tumors. (d) Ex vivo fluorescence imaging of

rn

the major organs (1-5: heart, liver, spleen, lung, kidney, respectively) and tumor at 48

Jo u

h after administration. (e) The growth curves of tumor upon different treatments (Dosage: 3.6 mg/kg CP‐NI, 2.0 mg/kg DOX; light treatment: 532 nm, 0.1 W/cm2 , 5 min). (f) Histological images of the tumor tissues after treatment and stained with H&E and Tunel. Reprinted with permission from Wiley-VCH [194]. Copyright 2016. 4.3. Light/pH/hypoxia stimuli-driven Recently, Chen et al. reported a study on a photothermal-pH- hypoxia responsive delivery system (TENAB NPs) [195]. A hypoxia-specific prodrug tirapazamine (TPZ) and pH-responsive photo-sensitizer ENAB were successfully encapsulated within a biocompatible eutectic phase change material (LASA, a mixture of linoleic acid and stearyl alcohol). Upon 808 nm laser irradiation, the LASA coat could be broken and melted down due to the photothermal effect of ENAB, triggering the release of TPZ. 45

Journal Pre-proof Meanwhile, NIR aza-BODIPY derivative ENAB could switch off charge-transfer state under acidic pH, simultaneously generating ROS for PDT and HT for PTT. Due to the oxygen-consuming PDT, the released TPZ can be activated by elevated hypoxia, and subsequently generate hydroxyl radical for amplified tumoricidal effect. Furthermore, due to the excellent photophysical properties, TENAB NPs could achieve multiple bioimaging, including fluorescence, PA, and photothermal imaging. By virtue of LASA’s tunable phase change and ENAB’s pH sensitivity, TENAB NPs

f

exhibited negligible phototoxicity to the skin and normal tissues. Thereafter, this

oo

multi-stimuli-responsive DDS displayed an extremely specific and synergistic

Jo u

rn

al

Pr

e-

pr

therapeutic effect with excellent skin protection (Fig. 20).

Fig. 20. Multi-stimuli responsive nanoplatform (TENAB NPs) for imaging-guided cancer photo-chemo therapy with inappreciable phototoxicity: (a) The mechanism of multi-stimuli responsive TENAB NPs for synergistic cancer photo-chemotherapy. (b) 46

Journal Pre-proof In vivo PA imaging of tumors site at different time points post- injection of TENAB NPs. (c) Tumor growth curves after various treatments. (d) Photographs and H&E histological analysis of mice skin after subcutaneous injection of various preparations and irradiation by LED (0.05 W/cm2 , 30 min). Reprinted with permission from Elsevier [195]. Copyright 2019. As previously mentioned, the combination of exogenous and endogenous stimuli could improve the accuracy and flexibility of targeted drug delivery, endowing the

f

nano-assemblies with multiple functions beyond drug delivery, such as PDT and

oo

imaging. Smart DDS requires an accurate response in a narrow window. However, for

pr

single exogenous stimulus-responsive nano-assemblies, the “on-off” switchable process is unlikely to be controlled at the cellular level due to the relatively low

e-

precision of the exogenous stimuli. In this regard, the exogenous/endogenous dual

Pr

stimuli-responsive nano-assemblies, which combine remote control and auto response, could achieve a much higher accuracy of regulation. Moreover, the complementarity

al

between exogenous and endogenous stimuli further strengthens the treatment effect and minimize the undesired side effect [196]. Despite the versatility and superiority of

rn

these complementary strategies, the concept is still too complicated. Most of the

Jo u

multi-stimuli responsive nano-assemblies still remain as proofs of the concept [197]. Therefore, to establish the translational potential of these systems, more evidence should be provided both in vitro and in vivo. 5. Bio-cleanable stimuli-responsive nano-assemblies Thus far, inorganic or organic-inorganic nano-assemblies have encountered immense obstacles in the process of further clinical translation, in comparison to organic nano-systems as most of these assemblies are undegradable or hardly degraded. In order to narrow the gap between scientific research and clinical development of nano-assemblies-based DDS, researchers have never cease to explore biodegradable or clearable NPs [198]. The size of nanoparticles can drastically impact 47

Journal Pre-proof the in vivo performance of nano-assemblies by altering their circulation time, biodistribution and excretion [199]. In fact, the NPs greater than 10 nm or incorporated with heavy metal components may accumulate in the reticuloendothelial system (RES, e.g., liver and spleen), resulting in low passive targeting specificity and long-term toxicity [200]. Whereas, NPs with small sizes (<5.5 nm) can be rapidly cleared by the kidney [201]. Thereby, clearable nano- materials present great potential in reducing the non-specific accumulation induced systemic toxicity. A variety of

f

ultra-small inorganic nanoclusters have been synthesized through various methods

oo

and principles, which is beneficial for the clinical translation due to their rapid

pr

excretion rates in vivo [202]. Recently, our group had synthesized hollow bismuth subcarbonate nanotubes (BNTs) for tumor-targeted imaging and chemoradiotherapy

e-

(Fig. 21). The BNTs with high length-diameter ratio were assembled from

Pr

renal-clearable ultrafine bismuth subcarbonate nanoclusters. In the meantime, chemotherapeutic drug, DOX was loaded into the hollow cavity of BNTs for further

al

tumor treatment. Upon reaching the acidic tumor microenvironment, these BNTs could disassemble into ultrafine nanoclusters, which enabled BNTs to realize the

rn

selective drug release of as well as kidney excretion, ensuring good biosafety.

Jo u

Moreover, the bismuth, having relatively high X-ray attenuation coefficient (5.74 cm2 /kg at 100 keV) further adds the value to BNTs by exhibiting high CT contrast effect which contributes to efficient CT imaging- guided therapy in the presence of exogenous light stimuli [203].

48

Jo u

rn

al

Pr

e-

pr

oo

f

Journal Pre-proof

Fig. 21. Renal-clearable bismuth subcarbonate nanotubes (BNTs) for tumor diagnosis and treatment. (a) Schematic illustration of assembly and disassembly of BNTs for tumor-targeted imaging-guided therapy and renal-clearance. (b) 3D CT images of rats with BNTs treatment. (c) Viability of Huh-7 cells with treatments of BNTs, BNTs/DOX, BNTs + X-ray or BNTs/DOX + X-ray. (d) The release profiles of DOX form BNTs/DOX at different pH values. (e) Bi content of the collected feces and

49

Journal Pre-proof urine at different time points, (f) Body weights variation. Reprinted with permission from the American Chemical Society [203]. Copyright 2018. Furthermore, Wei et al. [204] have also constructed a light-triggered renal-clearable nano-assembly to achieve a better biomedical application by synthesizing sub-6 nm CuS nanodots (CuSNDs)-sealed DOX- loaded MSNs (termed as MDNs). The remarkable photo-to-heat transducer and ultra-small CuS nanodots could control the drug release from the pores of MSNs upon laser irradiation. In this process, the MSNs

oo

f

were destroyed by the CuS induced HT and excreted rapidly from the living body. Subsequently, the ultra-small CuS nanodots with smaller size than the renal clearance

pr

threshold could be quickly excreted by the renal clearance pathway and guarantee

e-

enhanced biosafety. Therefore, this ingenious design is not only appealing to drug delivery but could simultaneously avoid long-term toxicity (Fig. 22). In general, these

Pr

stimuli-responsive renal-clearable NPs provide a new paradigm for engineering nanoparticle assemblies that can selectively target tumor sites while rapidly get

Jo u

rn

al

eliminated from the body after fully exerting the therapeutic effect.

50

al

Pr

e-

pr

oo

f

Journal Pre-proof

rn

Fig. 22. Highly efficient renal-clearable nanoparticles (CuSNDs) for cancer combination therapy: (a) Scheme for designing process of MDNs. (b) H&E, TUNEL,

Jo u

and Ki‐67 staining of the tumors after undergoing 21 d of different treatments. The tumor was found to be absent in MDNs plus laser group, Scale bars: 50 µm. Inductively coupled plasma mass spectrometer (ICP‐MS) analysis of the Si (c) or Cu (d) content in the major organs of mice after intravenous injection of MDNs (n=3). (e) Schematic illustration of MDNs on clearance function post intravenous injection. Reprinted with permission from Wiley-VCH [204]. Copyright 2017. 6. Conclusion and future perspectives In conclusion, the remotely controllable nano-assemblies provide an appealing concept for advanced DDSs. Each exogenous stimulus system has unique drug 51

Journal Pre-proof delivery manipulation. For instance, the diversity of light-sensitive substrates can achieve precise point-to-point manipulation, magnetic stimulation has no depth limitation and can serve as a compass to guide drug delivery, and acoustic stimulation is capable of influencing the interstitial spaces, improving the drug permeability. The common advantages of the external stimuli activated nano-assemblies are their non- invasive, temporal and spatial controllability. In addition, these controllable nano-assemblies are not just restricted in the application of drug delivery but are

f

capable of incorporating biosensing, medical imaging, early diagnosis, and therapy

oo

into one system.

pr

Recent advances in responsive nano-assemblies have witnessed tremendous contributions of inorganic nanomaterials such as UCNPs, magnetic ferrite

e-

nanohybrids, Au NPs, ultra-small CuS nanodots, etc. These inorganic nanomaterials

Pr

are attractive in exogenous, endogenous or combination of both stimuli system and have proved their importance in biomedical applications. Despite the varying degrees

al

of achievement, these NPs are still encountering long-term challenges for clinical translation. To guarantee the safety of the inorganic nano-assemblies, it is crucial to

rn

consider their degradation and excretion of from the body. Most of the strategies have

Jo u

been focused on surface modification, materials modification, and/or integration with highly biocompatible polymers according to the in vivo behaviors of nano-composites. The underlying issue is that the in vivo behavior and safety of nano-assemblies with multiple components are more complex to evaluate. Taking this into account, recent advanced renal-cleanable nano-assemblies, inspired an innovative nanotechnology, especially controllable renal-cleanable nano-assemblies, which are activated by various stimuli. They are gaining a momentum since rapid clearance significantly lowers the long-term toxicity of nanomaterials. Such triggered renal-clearable nano-system depends on the larger-to-small transition of assembled nanoparticles, and this process forces us to concern how to avoid the small molecule-protein interactions to smooth renal-clearance. 52

Journal Pre-proof Any innovation related to biomedical applications cannot be taken lightly. In future studies, researchers should figure out the in vivo clearance and degradation of both nanocarriers and active ingredients while designing functionalized nano-assemblies. Meanwhile, responsive nano-assemblies should be exploited extensively to expand the repertory of biodegradable and biocompatible nanomaterials with remotely controlled stimuli-responsive properties in order to boost the bench-to-bedside transition of the nano-assembly-based DDSs.

f

Stimuli- responsive nano-assemblies hold huge potential in improving the life

oo

quality of the patients by permitting accurate spatial-temporal control of drug delivery.

pr

Currently, several stimuli-responsive DDSs are already under clinical trials. For example, ThermoDox, the thermosensitive liposomal doxorubicin, has been approved

e-

for phase III clinical trial for primary liver cancer; and Opaxio, an enzyme-activated

Pr

polymeric nanoparticle, is in clinical trials for ovarian cancer and some other tumors [205-210]. However, the majority of the stimuli-responsive DDS is still at the

al

proof-of-concept stage and is far from clinical application. There are several factors that need to be considered to facilitate the translational process. First, an incomplete

rn

understanding of the mechanisms governing the physiochemical properties of the

Jo u

nano-assembly renders it difficult to realize “fabrication by design”, resulting in batch-to-batch variations unfavorable for industrialization. Moreover, scale-up synthesis needs to be validated since reaction conditions are much more difficult to control on a larger scale. Second, more systematic toxicological studies especially on the long-term toxicity of stimuli-responsive nano-assemblies are required, which has often been ignored in researches focusing more on assessing the efficacy. Notably, most studies only look into the major organs for biosafety evaluation, without considering that complex NPs can also end up in other tissues or specific cells. Third, many stimuli- responsive nano-assemblies are multicomponent systems designed to disintegrate in the body, which will inevitably render it very challenging to analyze the bio- nano interactions and dose-effect relationships. Finally, the economic 53

Journal Pre-proof considerations on DDS also play a role in the translation of these sophis ticated systems.

The

relatively

high

cost

for

manufacturing

those

advanced

stimuli-responsive assemblies and the protracted process of the regulatory process bring uncertainly to the financial success of such cutting-edge DDS. These issues will require continuous effort and persistent researches, along with close inter-discipline collaboration and academia- industry cooperation, which will eventually guarantee the clinical translation of those advanced responsive nano-assemblies in the future.

oo

f

Author contributions

D.L. and R.Q. conceived the ideas and outline, and revised the manuscript. F.L.,

pr

Y.Q. and J.L. wrote the manuscript, all authors edited and proofread it before submission. T.P. made a considerable contribution to the discussion of content and

e-

reviewing of the manuscript. Acknowledgements

Pr

This work was supported by the National Key Research and Development Program of China (2016YFA0203600); the National Natural Science Foundation of China

al

(31822019, 51703195, 91859116); the One Belt and One Road International Cooperation Project from Key Research and Development Program of Zhejiang

rn

Province (2019C04024); the Zhejiang Provincial Natural Science Foundation of China (LGF19C100002; and the Fundamental Research Funds for the Central

Jo u

Universities (2018QNA7020). We would like to thank the authors of the primary studies. Some of the figures in this article were created using BioRender biorender.com.

Declaration of Competing Interest The authors declare no conflict of interest. Reference [1] F. Li, J. Lu , X. Kong, T. Hyeon, D. Ling, Dynamic Nanoparticle Assemblies for Bio medical Applications, Adv. Mater. 29 (14) (2017) 1605897, doi:10.1002/adma.201605897. [2] F. Scaletti, J. Hard ie, Y.-W. Lee, D.C. Luther, M. Ray, V.M. Rotello, Protein delivery into cells using inorganic nanoparticle–protein supramolecular assemblies, Chem. Soc. Rev. 47 (10) (2018) 3421-3432, doi:10.1039/C8CS00008E. [3] N. Rabiee, M.T. Yaraki, S.M. Garakani, S.M. Garakan i, S. Ah madi, A. Lajevardi, M. Bagherzadeh, M. Rabiee, L. Tayebi, M. Tahriri, M.R. Hamblin, Recent advances in porphyrin -based nanocomposites 54

Journal Pre-proof for

effective

targeted

imaging

and

therapy,

Bio materials

232

(2020)

119707,

doi:10.1016/ j.bio materials.2019.119707. [4] J.Z. Du, H.J. Li, J. Wang, Tu mor-Acid ity-Cleavable Maleic Acid A mide (TACMAA): A Powerful Tool for Designing Smart Nanoparticles To Overco me Delivery Barriers in Cancer Nanomedicine, Acc. Chem. Res. 51 (11) (2018) 2848-2856, doi:10.1021/acs.accounts.8b00195. [5] H. Kuang, S.H. Ku, E. Ko kko li, The design of peptide-amphiphiles as functional ligands for liposomal anticancer drug and gene delivery, Adv. Drug Deliv. Rev. 110-111 (2017) 80-101, doi:10.1016/ j.addr.2016.08.005. [6] J.T. Huckaby, S.K. Lai, PEGy lation for enhancing nanoparticle diffusion in mucus, Adv. Drug Deliv. Rev. 124 (2018) 125-139, doi:10.1016/j.addr.2017.08.010. [7] C. Carvalho, R.X. Santos, S. Cardoso, S. Correia, P.J. Oliveira, M.S. Santos, P.I. Moreira,

f

Do xorubicin: the good, the bad and the ugly effect, Curr Med Chem 16 (25) (2009) 3267-3285,

oo

doi:10.2174/092986709788803312.

[8] A.A. Gabizon, Y. Pat il, N.M. La-Beck, New insights and evolving role o f pegylated liposomal doxorubicin in cancer therapy, Drug Resist Updat 29 (2016) 90-106, doi:10.1016/ j.drup.2016.10.003.

pr

[9] N. Kamaly, Z. Xiao, P.M. Valencia, A.F. Radovic-Moreno, O.C. Farokh zad, Targeted poly meric therapeutic nanoparticles: design, development and clin ical translation, Chem Soc Rev 41 (7) (2012)

e-

2971-3010, doi:10.1039/c2cs15344k.

[10] M.B. Violatto, E. Casarin, L. Talamin i, L. Russo, S. Baldan, C. Tondello, M. Messmer, E.

Pr

Hintermann, A. Rossi, A. Passoni, R. Bagnati, S. Biffi, C. Toffan in, S. Gimondi, S. Fu magalli, M.G. De Simoni, D. Barisani, M . Salmona, U. Christen, P. Invernizzi, P. Bigini, M. Morpurgo, Dexamethasone Conjugation to Biodegradable Avidin -Nucleic-Acid-Nano-Assemblies Pro motes

al

Selective Liver Targeting and Improves Therapeutic Efficacy in an Autoimmune Hepatit is Murine Model, ACS Nano 13 (4) (2019) 4410-4423, doi:10.1021/acsnano.8b09655.

rn

[11] P. Pradhan, J. Giri, F. Rieken, C. Koch, O. My khaylyk, M. Doblinger, R. Banerjee, D. Bahadur, C. Plank, Targeted temperature sensitive magnetic liposomes for thermo -chemotherapy, J Control Release

Jo u

142 (1) (2010) 108-121, doi:10.1016/ j.jconrel.2009.10.002. [12] N. Fo mina, J. Sankaranarayanan, A. Almutairi, Photochemical mechanis ms of light -triggered release

fro m

nanocarriers,

Adv.

Drug.

Deliv.

Rev.

64

(11)

(2012)

1005-1020,

doi:10.1016/ j.addr.2012.02.006.

[13] Y. Li, K. Xiao, W. Zhu, W. Deng, K.S. Lam, Stimuli-responsive cross-linked micelles for on-demand

drug

delivery

against

cancers, Adv. Drug. Deliv.

Rev.

66

(2014)

58-73,

doi:10.1016/ j.addr.2013.09.008. [14] Y. Zhang, J. Yu, H.N. Bo mba, Y. Zhu, Z. Gu , Mechanical Force-Triggered Drug Delivery, Chem. Rev. 116 (19) (2016) 12536-12563, doi:10.1021/acs.chemrev.6b00369. [15] D. Liu, F. Yang, F. Xiong, N. Gu, The Smart Drug Delivery System and Its Clin ical Potential, Theranostics 6 (9) (2016) 1306-1323, doi:10.7150/thno.14858. [16] Y. Wang, J. Chen, B. Yang, H. Qiao, L. Gao, T. Su, S. Ma, X. Zhang, X. Li, G. Liu, J. Cao, X. Chen, Y. Chen, F. Cao, In vivo MR and fluorescence dual-modality imaging of atherosclerosis characteristics in mice using profilin-1 targeted magnetic nanoparticles, Theranostics 6 (2) (2016) 272-286, doi:10.7150/thno.13350.

55

Journal Pre-proof [17] T. Boissenot, A. Bordat, E. Fattal, N. Tsapis, Ultrasoun d-triggered drug delivery for cancer treatment using drug delivery systems: Fro m theoretical considerations to practical applicat ions, J. Control. Release 241 (2016) 144-163, doi:10.1016/j.jconrel.2016.09.026. [18] Z. Luo, Y. Hu, K. Cai, X. Ding, Q. Zhang, M. Li, X. Ma, B. Zhang, Y. Zeng, P. Li, J. Li, J. Liu, Y. Zhao, Intracellular redo x-act ivated anticancer drug delivery by functionalized hollo w mesoporous silica

nanoreservoirs

with

tumor

specificity,

Bio materials

35

(27)

(2014)

7951-7962,

doi:10.1016/ j.bio materials.2014.05.058. [19] M. Vazzana, T. Andreani, J. Fangueiro, C. Faggio, C. Silva, A. Santin i, M .L. Garcia, A.M. Silva, E.B. Souto, Tramadol hydrochloride: pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems, Bio med. Pharmacother. 70 (2015) 234 -238, doi:10.1016/ j.biopha.2015.01.022.

f

[20] J. Liu, C. Detremb leur, S. Mornet, C. Jérô me, E. Duguet, Design of hybrid nanovehicles for

oo

remotely triggered drug release: an overview, J. Mater. Chem. B 3 (30) (2015) 6117-6147, doi:10.1039/ C5TB00664C.

[21] Y. Lu, A.A. Aimetti, R. Langer, Z. Gu, Bioresponsive materials, Nat. Rev. Mater. 2 (1) (2016)

pr

16075, doi:10.1038/natrev mats.2016.75.

[22] M. Kanamala, W.R. W ilson, M. Yang, B.D. Palmer, Z. Wu, Mechanisms and bio materials in

e-

pH-responsive tumour targeted drug delivery: A review, Bio materials 85 (2016) 152 -167, doi:10.1016/ j.bio materials.2016.01.061. drug

delivery

in

cancer

Pr

[23] J. Liu, Y. Huang, A. Ku mar, A. Tan, S. Jin, A. Mozhi, X.J. Liang, pH-sensitive nano-systems for therapy,

doi:10.1016/ j.biotechadv.2013.11.009.

Biotechnol

Adv

32

(4)

(2014)

693 -710,

al

[24] T. Fukino, H. Yamag ishi, T. Aida, Redo x-Responsive Molecular Systems and Materials, Adv. Mater. 29 (25) (2017), doi:10.1002/ad ma.201603888.

rn

[25] M. Karimi, A. Ghasemi, P. Sahandi Zangabad, R. Rahighi, S.M. Moosavi Basri, H. Mirshekari, M. Amiri, Z. Shafaei Pishabad, A. Aslani, M . Bo zorgo mid, D. Ghosh, A. Bey zavi, A. Vaseghi, A.R. Aref,

Jo u

L. Haghani, S. Bahrami, M .R. Hamb lin, Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems, Chem Soc Rev 45 (5) (2016) 1457-1501, doi:10.1039/c5cs00798d. [26] J. Mu, J. Lin, P. Huang, X. Chen, Develop ment of endogenous enzyme-responsive nanomaterials for theranostics, Chem. Soc. Rev. 47 (15) (2018) 5554-5573, doi:10.1039/c7cs00663b. [27] R. de la Rica, D. Aili, M.M. Stevens, Enzy me-responsive nanoparticles for drug release and diagnostics, Adv Drug Deliv Rev 64 (11) (2012) 967-978, doi:10.1016/j.addr.2012.01.002. [28] J. Hu, G. Zhang, S. Liu, En zy me-responsive polymeric assemblies, nanoparticles and hydrogels, Chem Soc Rev 41 (18) (2012) 5933-5949, doi:10.1039/c2cs35103j. [29] J. Mu, J. Lin, P. Huang, X. Chen, Develop ment of endogenous enzyme-responsive nanomaterials for theranostics, Chem Soc Rev 47 (15) (2018) 5554-5573, doi:10.1039/c7cs00663b. [30] S. Wang, G. Yu , Z. Wang, O. Jacobson, L.S. Lin, W. Yang, H. Deng, Z. He, Y. Liu, Z.Y. Chen, X. Chen, Enhanced Antitumor Efficacy by a Cascade of Reactive Oxygen Species Generation and Drug Release, Angew. Chem. Int. Ed. Engl. 58 (41) (2019) 14758-14763, doi:10.1002/anie.201908997. [31] W.C. Ballance, E.C. Qin, H.J.

Chung, M.U. Gillette, H. Kong, Reactive o xygen

species-responsive drug delivery systems for the treat ment of neurodegenerative diseases, Bio materials 217 (2019) 119292, doi:10.1016/j.bio materials.2019.119292. 56

Journal Pre-proof [32] X. Xu, P.E. Saw, W. Tao, Y. Li, X. Ji, S. Bhasin, Y. Liu, D. Ayyash, J. Ras mussen, M. Huo, J. Shi, O.C. Faro khzad, ROS-Responsive Polyprodrug Nanoparticles for Triggered Drug Delivery and Effective Cancer Therapy, Adv Mater 29 (33) (2017), doi:10.1002/adma.201700141. [33] R. Ku mari, D. Sunil, R.S. Ningthoujam, Hypo xia -responsive nanoparticle based drug delivery systems in cancer therapy: An up-to-date review, J Control. Release 319 (2019) 135-156, doi:10.1016/ j.jconrel.2019.12.041. [34] R. Ku mari, D. Sunil, R.S. Ningthoujam, Hypo xia -responsive nanoparticle based drug delivery systems in cancer therapy: An up-to-date review, J Control Release 319 (2020) 135-156, doi:10.1016/ j.jconrel.2019.12.041. [35] C. Qian, J. Yu, Y. Chen, Q. Hu, X. Xiao, W. Sun, C. Wang, P. Feng, Q.D. Shen, Z. Gu, Light-Activated Hypoxia -Responsive Nanocarriers for Enhanced Anticancer Therapy, Adv Mater 28

f

(17) (2016) 3313-3320, doi:10.1002/ad ma.201505869.

oo

[36] G. Yang, S.Z.F. Phua, W.Q. Lim, R. Zhang, L. Feng, G. Liu, H. Wu, A.K. Bindra, D. Jana, Z. Liu, Y. Zhao, A Hypo xia-Responsive Albu min-Based Nanosystem for Deep Tu mor Penetration and Excellent Therapeutic Efficacy, Adv Mater 31 (25) (2019) e1901513, doi:10.1002/adma.201901513.

pr

[37] W. Yin , M. Qiang, W. Ke, Y. Han, J.F. Mukerabigwi, Z. Ge, Hypo xia -responsive block copolymer rad iosensitizers as anticancer drug nanocarriers for enhanced chemoradiotherapy of bulky

e-

solid tumors, Biomaterials 181 (2018) 360-371, doi:10.1016/j.bio materials.2018.08.014. [38] M. MJ, Chemical properties of antibacterials and their uniqueness, 1 ed., Springer US, 2012.

Pr

[39] S. Kalepu, V. Nekkanti, Improved delivery of poorly soluble co mpounds using nanoparticle technology: a review, Drug Deliv Transl Res 6 (3) (2016) 319-332, doi:10.1007/s13346-016-0283-1. [40] H.J. Kim, T. Kim, M. Lee, Responsive nanostructures from aqueous assembly of rigid -flexib le

al

block molecules, Acc Chem Res 44 (1) (2011) 72-82, doi:10.1021/ar100111n. [41] Y. Guo, K. Jiang, Z. Shen, G. Zheng, L. Fan, R. Zhao, J. Shao, A Small Mo lecule Nanodrug by

rn

Self-Assembly of Dual Anticancer Drugs and Photosensitizer for Synergistic near-Infrared Cancer Theranostics, ACS Appl. Mater. Interfaces 9 (50) (2017) 43508-43519, doi:10.1021/acsami.7b14755.

Jo u

[42] H. Acar, S. Srivastava, E.J. Chung, M.R. Schnorenberg, J.C. Barrett, J.L. LaBelle, M. Tirrell, Self-assembling peptide-based building blocks in medical applicat ions, Adv. Drug. Deliv. Rev. 110-111 (2017) 65-79, doi:10.1016/j.addr.2016.08.006. [43] M. Kang, P. Zhang, H. Cu i, S.M. Loverde, pi-pi Stacking Mediated Ch irality in Functional Supramo lecular

Filaments,

Macromo lecules

49

(3)

(2016)

994-1001,

doi:10.1021/acs.macro mol.5b 02148. [44] S. Santoso, W. Hwang, H. Hart man, S. Zhang, Self-assembly of Surfactant-like Peptides with Variable Glycine Tails to Form Nanotubes and Nanovesicles, Nano Lett. 2 (7) (2002) 687 -691, doi:10.1021/nl025563i. [45] M. Peng, S. Qin, J. Huizhen, D.-W. Zheng, L. Rong, X.-Z. Zhang, Self-delivery of a peptide-based prodrug for tumor-targeting therapy, Nano Res. 9 (2016) 663–673, doi:10.1007/s12274-015-0945-1. [46] T. Zhong, R. Huang, L. Tan, A mphiphilic drug–drug assembly via dual-responsive linkages for small-mo lecule

anticancer

d rug

delivery,

RSC

Adv.

6

(71)

(2016)

66420-66430,

doi:10.1039/ C6RA 15675D.

57

Journal Pre-proof [47] J. Andrew MacKay, M. Chen, J.R. McDaniel, W. Liu, A.J. Simn ick, A. Chilkoti, Self-assembling chimeric polypeptide–doxorubicin conjugate nanoparticles that abolish tumours after a single injection, Nat. Mater. 8 (12) (2009) 993-999, doi:10.1038/n mat2569. [48] D. Zhang, G.B. Qi, Y.X. Zhao, S.L. Qiao, C. Yang, H. Wang, In Situ Format ion of Nanofibers fro m Purpurin18-Peptide Conjugates and the Assembly Induced Retention Effect in Tu mor Sites, Adv. Mater. 27 (40) (2015) 6125-6130, doi:10.1002/ad ma.201502598. [49] S.D. Undevia, G. Go mez-Abuin, M.J. Ratain, Pharmacokinetic variability of anticancer agents, Nat. Rev. Cancer 5 (6) (2005) 447-458, doi:10.1038/nrc1629. [50] A.G. Cheetham, R.W. Chakroun, W. Ma, H. Cui, Self -assembling prodrugs, Chem. Soc. Rev. 46 (21) (2017) 6638-6663, doi:10.1039/ C7CS00521K. [51] R.H. Prabhu, V.B. Patravale, M .D. Joshi, Poly meric nanoparticles for targeted treatment in

f

oncology: current insights, Int. J. Nanomedicine 10 (2015) 1001-1018, doi:10.2147/ijn.S56932.

oo

[52] D. Neradovic, C.F. van Nostrum, W.E. Hennink, Thermo responsive Polymeric M icelles with Controlled Instability Based on Hydrolytically Sensitive N-Isopropylacrylamide Copoly mers, Macromolecules 34 (22) (2001) 7589-7591, doi:10.1021/ ma011198q.

pr

[53] Z. Ge, S. Liu, Functional b lock copoly mer assemblies responsive to tumor and intracellu lar microenvironments for site-specific drug delivery and enhanced imaging performance, Chem. Soc. Rev.

e-

42 (17) (2013) 7289-7325, doi:10.1039/c3cs60048c .

[54] H. Che, J.C.M. van Hest, Stimu li-responsive polymersomes and nanoreactors, J. Mater. Chem. B 4

Pr

(27) (2016) 4632-4647, doi:10.1039/ C6TB01163B.

[55] C. Oerlemans, W. Bult, M. Bos, G. Storm, J.F. Nijsen, W.E. Hennink, Poly meric micelles in doi:10.1007/s11095-010-0233-4.

al

anticancer therapy: targeting, imag ing and triggered release, Pharm. Res. 27 (12) (2010) 2569-2589, [56] H. Wei, X. Zhang, C. Cheng, S.-X. Cheng, R.-X. Zhuo, Self-assembled, thermosensitive micelles

rn

of a star block copoly mer based on PMMA and PNIPAAm for controlled drug delivery, Bio materials 28 (1) (2007) 99-107, doi:10.1016/j.bio materials.2006.08.030.

Jo u

[57] E. Rideau, R. Dimova, P. Schwille, F.R. Wurm, K. Landfester, Liposomes and polymersomes: a comparative review towards cell mimicking, Chem. Soc. Rev. 47 (23) (2018) 8572-8610, doi:10.1039/ C8CS00162F.

[58] H. Zhang, Y. Zhai, J. Wang, G. Zhai, New p rogress and prospects: The application of nanogel in drug delivery, Mater. Sci. Eng. C 60 (2016) 560-568, doi:10.1016/j.msec.2015.11.041. [59] I. Willner, Stimu li-Controlled Hydrogels and Their Applications, Accounts Chem. Res. 50 (4) (2017) 657-658, doi:10.1021/acs.accounts.7b00142. [60] L. Han, Y. Zhang, X. Lu , K. Wang, Z. Wang, H. Zhang, Polydopamine Nanoparticles Modulating Stimu li-Responsive PNIPAM Hydrogels with Cell/Tissue Adhes iveness, ACS Appl. Mater. Interfaces 8 (42) (2016) 29088-29100, doi:10.1021/acsami.6b11043. [61] D.D. Lasic, Novel applications of liposomes, Trends Biotechnol. 16 (7) (1998) 307 -321, doi:10.1016/s0167-7799(98)01220-7. [62] D. Papahadjopoulos, K. Jacobson, S. Nir, T. Isac, Phase transitions in phospholipid vesicles. Fluorescence polarization and permeability measurements concerning the effect of temperature and cholesterol, Biochim. Biophys. Acta 311 (3) (1973) 330-348, doi:10.1016/0005-2736(73)90314-3.

58

Journal Pre-proof [63] E. A mstad, J. Kohlbrecher, E. Mü ller, T. Schweizer, M. Textor, E. Reimhult, Triggered Release fro m Liposomes through Magnetic Actuation of Iron Oxide Nanoparticle Containing Membranes, Nano Lett. 11 (4) (2011) 1664-1670, doi:10.1021/n l2001499. [64] D.C. Soares, M.C. de Oliveira, R.G. dos Santos, M.S. Andrade, J.M. Vilela, V.N. Cardoso, G.A. Ramaldes,

Liposomes

rad iolabeled

with

159Gd -DTPA-BMA:

preparation, physicochemical

characterizat ion, release profile and in vitro cytotoxic evaluation, Eur J Pharm. Sci. 42 (5) (2011) 462-469, doi:10.1016/ j.ejps.2011.01.010. [65] X. Xu, L. Zhang, A.G. Assanhou, L. Wang, Y. Zhang, W. Li, L. Xue, R. Mo, C. Zhang, Acid/redox dual-act ivated liposomes for tumor-targeted drug delivery and enhanced therapeutic efficacy, RSC Adv. 5 (83) (2015) 67803-67808, doi:10.1039/ C5RA 06445G. [66] A. Arouri, O.G. Mouritsen, Phospholipase A(2)-susceptible liposomes of anticancer double

f

lipid-prodrugs, Eur J Pharm. Sci. 45 (4) (2012) 408-420, doi:10.1016/j.ejps.2011.09.013.

oo

[67] A. Yavlovich, B. Smith, K. Gupta, R. Blu menthal, A. Puri, Light -sensitive lip id-based nanoparticles for drug delivery: design principles and future considerations for biological applications, Mol. Membr. Biol. 27 (7) (2010) 364-381, doi:10.3109/ 09687688.2010.507788.

pr

[68] D. Liu, B. Chen, Y. Mo, Z. Wang, T. Qi, Q. Zhang, Y. Wang, Redo x-Activated Porphyrin-Based Liposome Remote-Loaded with Indoleamine 2,3-Dio xygenase (IDO) Inhibitor for Synergistic

e-

Photoimmunotherapy through Induction of Immunogenic Cell Death and Blockage of IDO Pathway, Nano Letters 19 (10) (2019) 6964-6976, doi:10.1021/acs.nanolett.9b02306.

Pr

[69] C. Burda, X. Chen, R. Narayanan, M.A. El-Sayed, Chemistry and properties of nanocrystals of different shapes, Chem. Rev. 105 (4) (2005) 1025-1102, doi:10.1021/cr030063a. [70] P.O. Anikeeva, J.E. Halpert, M.G. Bawendi, V. Bulović, Quantum Dot Light-Emitt ing Devices

al

with Electrolu minescence Tunable over the Entire Vis ible Spectru m, Nano Lett. 9 (7) (2009) 2532-2536, doi:10.1021/nl9002969.

rn

[71] P.C. Ohara, D.V. Leff, J.R. Heath, W.M. Gelbart, Crystallizat ion of opals from polydisperse nanoparticles, Phys. Rev. Lett. 75 (19) (1995) 3466-3469, doi:10.1103/ PhysRevLett.75.3466.

Jo u

[72] A.M. Kalsin, M. Fialko wski, M. Paszewski, S.K. Smou kov, K.J. Bishop, B.A. Grzybowski, Electrostatic self-assembly of binary nanoparticle crystals with a diamond -like lattice, Science 312 (5772) (2006) 420-424, doi:10.1126/science.1125124. [73] Z. Sun, F. Bai, H. Wu, S.K. Schmitt, D.M. Boye, H. Fan, Hydrogen -bonding-assisted self-assembly: monodisperse hollow nanoparticles made easy, J. Am. Chem. Soc. 131 (38) (2009) 13594-13595, doi:10.1021/ja905240w. [74] Y. Lalatonne, J. Richard i, M. Pileni, Van der Waals versus dipolar forces controlling mesoscopic organizations of magnetic nanocrystals, Nat. Mater. 3 (2004) 121-125, doi:10.1038/n mat1054. [75] Z. Nie, A. Petukhova, E. Ku macheva, Properties and emerg ing applications of self-assembled structures

made

fro m

inorganic

nanoparticles,

Nat.

Nanotech.

5

(1)

(2010)

15-25,

doi:10.1038/nnano.2009.453. [76] G.Y. Tonga, D.F. Moyano, C.S. Kim, V.M. Rotello, Inorganic Nanoparticles for Therapeutic Delivery: Trials, Tribulat ions and Pro mise, Curr. Opin. Co lloid Interface Sci. 19 (2) (2014) 49-55, doi:10.1016/ j.cocis.2014.03.004. [77] G.Y. Tonga, K. Saha, V.M. Rotello, 25th anniversary article: interfacing nanoparticles and biology: new strategies for biomedicine, Adv. Mater. 26 (3) (2014) 359-370, doi:10.1002/adma.201303001. 59

Journal Pre-proof [78] B.H. Kim, N. Lee, H. Kim, K. An, Y.I. Park, Y. Choi, K. Sh in, Y. Lee, S.G. Kwon, H.B. Na, J.-G. Park, T.-Y. Ahn, Y.-W. Kim, W.K. Moon, S.H. Choi, T. Hyeon, Large-Scale Synthesis of Uniform and Extremely Small-Sized Iron Oxide Nanoparticles for High-Resolution T1 Magnetic Resonance Imaging Contrast Agents, Journal of the American Chemical Society 1 33 (32) (2011) 12624-12631, doi:10.1021/ ja203340u. [79] J.J. Giner-Casares, M. Henriksen-Lacey, M. Coronado-Puchau, L.M. Liz-Marzán, Inorganic nanoparticles for bio medicine: where materials scientists meet medical research, Mater. Today 19 (1) (2016) 19-28, doi:10.1016/j.mattod.2015.07.004. [80] D. Ni, W. Bu, E.B. Ehlerding, W. Cai, J. Shi, Engineering of inorganic nanoparticles as magnetic resonance

imaging

contrast

agents,

Chem.

Soc.

Rev.

46

(23)

(2017)

7438-7468,

doi:10.1039/c7cs00316a.

f

[81] F. Tang, L. Li, D. Chen, Mesoporous silica nanoparticles: synthesis, b iocompatibility and drug

oo

delivery, Adv. Mater. 24 (12) (2012) 1504-1534, doi:10.1002/ad ma.201104763. [82] H. Wu, F. Li, S. Wang, J. Lu, J. Li, Y. Du, X. Sun, X. Chen, J. Gao, D. Ling, Ceria nanocrystals decorated mesoporous silica nanoparticle based ROS-scavenging tissue adhesive for highly efficient

pr

regenerative wound healing, Biomaterials 151 (2018) 66-77, doi:10.1016/ j.b io materials.2017.10.018. [83] J. Wen, K. Yang, F. Liu, H. Li, Y. Xu, S. Sun, Diverse gatekeepers for mesoporous silica

e-

nanoparticle based drug delivery systems, Chem. Soc. Rev. 46 (19) (2017) 6024-6045, doi:10.1039/c7cs00219j.

Pr

[84] V. Raeesi, L.Y. Chou, W.C. Chan, Tuning the Drug Loading and Release of DNA -Assembled Gold-Nanorod Superstructures, Adv. Mater. 28 (38) (2016) 8511-8518, doi:10.1002/adma.201600773. [85] T. Wang, M. Yang, J. Huang, Y. Zhao, H. Wang, S. Leng, J. Chen, G. Sun, J. Liu, NIR-to-NIR

al

UCL/T1-weighted MR/CT mu ltimodal imaging by NaYbF4:Tm@NaGd F4:Yb -PVP upconversion nanoparticles, Sci. Bulletin 62 (13) (2017) 903-912, doi:10.1016/ j.scib.2017.05.028.

rn

[86] D. Ling, W. Park, S.-j. Park, Y. Lu, K.S. Kim, M.J. Hackett, B.H. Kim, H. Yim, Y.S. Jeon, K. Na, T. Hyeon, Multifunctional Tu mo r pH-Sensitive Self-Assembled Nanoparticles for Bimodal Imag ing

Jo u

and Treatment of Resistant Heterogeneous Tumors, J. A m. Chem. Soc. 136 (15) (2014) 5647-5655, doi:10.1021/ ja4108287.

[87] Y. Liu, X. Yang, Z. Huang, P. Huang, Y. Zhang, L. Deng, Z. Wang, Z. Zhou, Y. Liu, H. Kalish, N.M. Khachab, X. Chen, Z. Nie, Magneto-Plas monic Janus Vesicles fo r Magnetic Field-Enhanced Photoacoustic and Magnetic Resonance Imaging of Tu mors, Angew. Chem. Int. Ed. Engl. 55 (49) (2016) 15297-15300, doi:10.1002/anie.201608338. [88] H. Deng, F. Dai, G. Ma, X. Zhang, Theranostic Gold Nano micelles made fro m Bioco mpatible Co mb-like Po ly mers for Thermochemotherapy and Multifunctional Imag ing with Rap id Clearance, Adv. Mater. 27 (24) (2015) 3645-3653, doi:10.1002/ad ma.201501420. [89] J. Lu, J. Sun, F. Li, J. Wang, J. Liu, D. Kim, C. Fan, T. Hyeon, D. Ling, Highly Sensitive Diagnosis of Small Hepatocellular Carcino ma Using pH -Responsive Iron Oxide Nanocluster Assemblies, J. Am. Chem. Soc. 140 (32) (2018) 10071-10074, doi:10.1021/jacs.8b04169. [90] L. Qiu , T. Chen, I. Öçsoy, E. Yasun, C. Wu, G. Zhu, M. You, D. Han, J. Jiang, R. Yu, W. Tan, A Cell-Targeted, Size-Photocontrollable, Nuclear-Uptake Nanodrug Delivery System for Drug-Resistant Cancer Therapy, Nano Lett. 15 (1) (2015) 457-463, doi:10.1021/nl503777s.

60

Journal Pre-proof [91] D. Manna, T. Udayabhaskararao, H. Zhao, R. Klajn, Orthogonal light -induced self-assembly of nanoparticles using differently substituted azobenzenes, Angew. Chem. Int. Ed . Eng l. 54 (42) (2015) 12394-12397, doi:10.1002/anie.201502419. [92] X. Liu, T. Sun, J. Hu, S. Wang, Co mposites of metal-organic frameworks and carbon-based materials: Preparat ions, functionalities and applications, J. Mater. Chem. A 4 (2016) 3584-3616, doi:10.1039/ C5TA09924B. [93] R. Ricco, L. Malfatti, M . Takahashi, A.J. Hill, P. Falcaro, Applications of magnetic metal–organic framework composites, J. of Mater. Chem. A 1 (42) (2013) 13033-13045, doi:10.1039/ C3TA13140H. [94] T. Kitao, Y. Zhang, S. Kitagawa, B. Wang, T. Uemura, Hybridization of MOFs and polymers, Chem. Soc. Rev. 46 (11) (2017) 3108-3133, doi:10.1039/ C7CS00041C. [95] C.D. Wu, M. Zhao, Incorporation of Molecular Catalysts in Metal -Organic Frameworks for

f

Highly Efficient Heterogeneous Catalysis, Adv. Mater. 29 (14) (2017), doi:10.1002/ad ma.201605446.

oo

[96] H. Furu kawa, K.E. Cordova, M. O'Keeffe, O.M . Yaghi, The chemistry and applications of metal-organic frameworks, Science 341 (6149) (2013) 1230444, doi:10.1126/science.1230444. [97] J. Lee, O.K. Farha, J. Roberts, K.A. Scheidt, S.T. Nguyen, J.T. Hupp, Metal-organic framework

pr

materials as catalysts, Chem. Soc. Rev. 38 (5) (2009) 1450-1459, doi:10.1039/b807080f. [98] L. Ma, C. Abney, W. Lin, Enantioselective catalysis with homochiral metal–organic frameworks,

e-

Chem. Soc. Rev. 38 (5) (2009) 1248-1256, doi:10.1039/ B807083K.

[99] L. Ma, J.M . Falko wski, C. Abney, W. Lin, A series of isoreticular chiral metal-organic

Pr

frameworks as a tunable platform for asy mmetric catalysis, Nat. Chem. 2 (10) (2010) 838 -846, doi:10.1038/nchem.738.

[100] C.A. Kent, B.P. Mehl, L. Ma, J.M. Papanikolas, T.J. Meyer, W. Lin, Energy transfer dynamics in

al

metal-organic frameworks, J. Am. Chem. Soc. 132 (37) (2010) 12767-12769, doi:10.1021/ ja102804s. [101] Z. Xie, L. Ma, K.E. deKra fft, A. Jin, W. Lin, Porous Phosphorescent Coordination Polymers for

rn

Oxygen Sensing, J. Am. Chem. Soc. 132 (3) (2010) 922-923, doi:10.1021/ja909629f. [102] B. Chen, S. Xiang, G. Qian, Metal-organic frameworks with functional pores for recognition of

Jo u

small molecules, Acc. Chem. Res. 43 (8) (2010) 1115-1124, doi:10.1021/ar100023y. [103] P. Horcajada, C. Serre, M. Vallet-Regi, M. Sebban, F. Tau lelle, G. Ferey, Metal-organic frameworks as efficient materials for drug delivery, Angew. Chem. Int. Ed Engl. 45 (36) (2006) 5974-5978, doi:10.1002/anie.200601878. [104] P. Horcajada, C. Serre, G. Maurin, N.A. Ramsahye, F. Balas, M. Vallet-Regi, M. Sebban, F. Taulelle, G. Ferey, Flexible porous metal-organic frameworks for a controlled drug delivery, J. A m. Chem. Soc. 130 (21) (2008) 6774-6780, doi:10.1021/ja710973k. [105] J. An, S.J. Geib, N.L. Rosi, Cat ion-Triggered Drug Release fro m a Porous Zinc−Adeninate Metal−Organic Framework, J. Am. Chem. Soc. 131 (24) (2009) 8376-8377, doi:10.1021/ ja902972w. [106] L. Catala, F. Vo latron, D. Brin zei, T. Mallah, Functional coordination nanoparticles, Inorg. Chem. 48 (8) (2009) 3360-3370, doi:10.1021/ic8012574. [107] W. Lin, W.J. Rieter, K.M. Tay lor, Modular synthesis of functional nanoscale coordination polymers, Angew. Chem. Int. Ed Engl. 48 (4) (2009) 650-658, doi:10.1002/anie.200803387. [108] A.M . Spo koyny, D. Kim, A. Su mrein, C.A. M irkin, Infin ite coordination poly mer nano - and microparticle structures, Chem. Soc. Rev. 38 (5) (2009) 1218-1227, doi:10.1039/ B807085G.

61

Journal Pre-proof [109] K.M. Tay lor-Pashow, J. Della Rocca, Z. Xie, S. Tran, W. Lin, Postsynthetic modifications of iron-carbo xy late nanoscale metal-o rganic framewo rks for imaging and drug delivery, J. A m. Chem. Soc. 131 (40) (2009) 14261-14263, doi:10.1021/ ja906198y. [110] S. Begu m, Z. Hassan, S. Brase, C. Woll, M. Tsotsalas, Metal-Organic Framework-Temp lated Bio materials: Recent Progress in Synthesis, Functionalization, and Applications, Acc Chem Res 52 (6) (2019) 1598-1610, doi:10.1021/acs.accounts.9b00039. [111] M.X. Wu, Y.W. Yang, Metal-Organic Framework (M OF)-Based Drug/Cargo Delivery and Cancer Therapy, Adv Mater 29 (23) (2017), doi:10.1002/ad ma.201606134. [112] X. Yang, Y. Wang, W. Qi, J. Zhang, L. Zhang, R. Huang, R. Su, Z. He, Photo -Induced Poly merization and Reconfigurable Assembly of Mult ifunctional Ferrocene -Tyrosine, Small 14 (25) (2018) e1800772, doi:10.1002/s mll.201800772.

f

[113] X. Zhou, Y. Li, Y. Xing, J. Li, X. Jiang, Effects of the preparation method of Pt/g -C3N4

oo

photocatalysts on their efficiency for v isible-light hydrogen production, Dalton Trans. 48 (40) (2019) 15068-15073, doi:10.1039/c9dt02938a.

[114] L. Fath-Bayati, M . Vasei, E. Sharif-Paghaleh, Optical fluorescence imag ing with shortwave 23 (12) (2019) 7905-7918, doi:10.1111/jcmm.14670.

pr

infrared light emitter nanomaterials for in v ivo cell tracking in regenerative med icine, J. Cell Mo l. Med.

e-

[115] B. Casin i, B. Tuvo, M.L. Cristina, A.M. Spagnolo, M. Totaro, A. Baggiani, G.P. Priv itera, Evaluation of an Ultravio let C (UVC) Light-Emitting Device for Disinfection of High Touch Surfaces

Pr

in Hospital Critical Areas, Int. J. Environ. Res. Public doi:10.3390/ ijerph16193572.

Health 16 (19) (2019) 35 72,

[116] S.H. Yun, S.J.J. Kwo k, Light in diagnosis, therapy and surgery, Nat. Bio med. Eng. 1 (1) (2017)

al

0008, doi:10.1038/s41551-016-0008

[117] J. Zhou, Z. Liu, F. Li, Upconversion nanophosphors for small -animal imaging, Chem. Soc. Rev.

rn

41 (3) (2012) 1323-1349, doi:10.1039/c1cs15187h. [118] M. Brenner, V.J. Hearing, The protective role of melanin against UV damage in hu man skin,

Jo u

Photochem. Photobiol. 84 (3) (2008) 539-549, doi:10.1111/j.1751-1097.2007.00226.x. [119] C.E. Lan, Effects and interactions of increased environmental temperature and UV rad iation on photoageing and photocarcinogenesis of the skin, Exp . Dermatol. 28 Suppl 1 (2019) 23-27, doi:10.1111/exd.13818.

[120] X. Qu, W. Song, Z. Shen, A Highly Selective NIR Fluorescent Turn -on Probe for Hydro xyl Radical

and

Its

Application

in

Liv ing

Cell

Images,

Front.

Chem.

7

(2019)

598,

doi:10.3389/fchem.2019.00598. [121] J. Shen, G. Chen, T.Y. Ohulchanskyy, S.J. Kesseli, G. Han, Tunable Near Infrared to Ultraviolet Upconversion Lu minescence Enhancement in (α ㎞ aYF4:Yb ,Tm)/CaF2 Core/Shell Nanoparticles for In situ Real‐ time Recorded Bioco mpatible Photoactivation, Small 9 (19) (2013) 3213-3217, doi:10.1002/smll.201300234. [122] M. Karimi, P. Sahandi Zangabad, S. Baghaee-Ravari, M. Ghazadeh, H. Mirshekari, M.R. Hamblin, Smart Nanostructures for Cargo Delivery: Uncaging and Activating by Light, J. A m. Chem. Soc. 139 (13) (2017) 4584-4610, doi:10.1021/jacs.6b08313.

62

Journal Pre-proof [123] S. Ren, X. Cheng, M. Chen, C. Liu, P. Zhao, W. Huang, J. He, Z. Zhou, L. Miao, Interfaces, Hypotoxic and Rap idly Metabolic PEG-PCL-C3-ICG Nanoparticles for Fluorescence-Gu ided Photothermal/Photodynamic Therapy against OSCC, A CS Appl. Mater. Interface s 9 (37) (2017) 31509-31518, doi:10.1021/acsami.7b09522. [124] V. Shanmugam, S. Selvaku mar, C.-S. Yeh, Near-infrared light-responsive nanomaterials in cancer therapeutics, Chem. Soc. Rev. 43 (17) (2014) 6254-6287, doi:10.1039/ C4CS00011K. [125] F. Yan, W. Duan, Y. Li, H. Wu, Y. Zhou, M. Pan, H. Liu, X. Liu, H. Zheng, NIR-Laser-Controlled Drug Release fro m DOX/ IR-780-Loaded Temperature-Sensitive-Liposomes for Chemo-Photothermal Synergistic Tu mo r Therapy, Theranostics 6 (13) (2016)

2337-2351,

doi:10.7150/thno.14937. [126] Y. Yuan, J. Liu, B. Liu, Conjugated-Polyelectrolyte-Based Polyprodrug: Targeted and

f

Image-Gu ided Photodynamic and Chemotherapy with On-Demand Drug Release upon Irradiation with

oo

a Single Light Source, Angew. Chem. Int. Ed. 53 (28) (2014) 7163-7168, doi:10.1002/anie.201402189. [127] F. Mohammed, W. Ke, J.F. Mukerabig wi, A.A. -W.M. M. Japir, A. Ibrahim, Y. Wang, Z. Zha, N. Lu, M. Zhou, Z. Ge, ROS-Responsive Poly meric Nanocarriers with Photoinduced Exposure of (2019) 31681-31692, doi:10.1021/acsami.9b10950.

pr

Cell-Penetrating Moiet ies for Specific Intracellu lar Drug Delivery, A CS Appl. Mater. Interfaces 11 (35)

e-

[128] J. Li, C. Sun, W. Tao, Z. Cao, H. Qian, X. Yang, J. Wang, Photoinduced PEG deshielding fro m ROS-sensitive linkage-bridged block copoly mer-based nanocarriers for on-demand drug delivery,

Pr

Biomaterials 170 (2018) 147-155, doi:10.1016/j.bio materials.2018.04.015. [129] J. Li, K. Wei, S. Zuo, Y. Xu, Z. Zha, W. Ke, H. Chen, Z. Ge, Light -Triggered Clustered Vesicles with Self-Supplied Oxygen and Tissue Penetrability for Photodynamic Therapy agains t Hypoxic

al

Tumor, Adv. Funct. Mater. 27 (33) (2017) 1702108, doi:10.1002/adfm.201702108. [130] L. Zhang, Y. Qin, Z. Zhang, F. Fan, C. Huang, L. Lu, H. Wang, X. Jin, H. Zhao, D. Kong, C. chemo-photothermal

rn

Wang, H. Sun, X. Leng, D. Zhu, Dual pH/reduction-responsive hybrid polymeric micelles for targeted co mbination

therapy,

Acta

Bio mater.

75

(2018)

371 -385,

Jo u

doi:10.1016/ j.actbio.2018.05.026.

[131] M. Song, N. Liu, L. He, G. Liu, D. Ling, X. Su, X. Sun, Porous hollow palladiu m nanoplatform for imaging-guided trimodal chemo-, photothermal-, and radiotherapy, Nano Res. 11 (5) (2018) 2796-2808, doi:10.1007/s12274-017-1910-y. [132] Z. Cao, Y. Ma, C. Sun, Z. Lu , Z. Yao, J. Wang, D. Li, Y. Yuan, X. Yang, ROS-Sensitive Poly meric Nanocarriers with Red Light-Activated Size Shrinkage for Remotely Controlled Drug Release, Chem. Mater. 30 (2) (2018) 517-525, doi:10.1021/acs.chemmater.7b 04751. [133] F. Yu, F. Zhang, L. Tang, J. Ma, D. Ling, X. Chen, X. Sun, Redo x-Responsive Dual Chemophotothermal Therapeutic Nano medicine for Imaging-Gu ided Co mb inational Therapy, J. Mater. Chem. B 6 (33) (2018) 5362-5367, doi:10.1039/C8TB01360H. [134] Z. Gu, L. Yan, G. Tian, S. Li, Z. Chai, Y. Zhao, Recen t advances in design and fabrication of upconversion nanoparticles and their safe theranostic applications, Adv. Mater. 25 (28) (2013) 3758-3779, doi:10.1002/adma.201301197. [135] X. Li, F. Zhang, D. Zhao, Lab on upconversion nanoparticles: optical properties and applications engineering

via

designed

nanostructure,

Chem.

Soc.

Rev.

44

(6)

(2015)

1346-1378,

doi:10.1039/c4cs00163j. 63

Journal Pre-proof [136] L. Beaute, N. McClenaghan, S. Leco mmandou x, Photo -triggered poly mer nano medicines: Fro m mo lecular mechanis ms to therapeutic applications, Adv. Drug Deliv. Rev. 138 (2019) 148 -166, doi:10.1016/ j.addr.2018.12.010. [137] M.K. Gnanasammandhan, N.M. Idris, A. Bansal, K. Huang, Y. Zhang, Near-IR photoactivation using mesoporous silica-coated NaYF4:Yb,Er/Tm upconversion nanoparticles, Nat. Protoc. 11 (4) (2016) 688-713, doi:10.1038/nprot.2016.035. [138] J. Shen, L. Zhao, G. Han, Lanthanide-doped upconverting luminescent nanoparticle platforms for optical imag ing-guided drug delivery and therapy, Adv. Drug Deliv. Rev. 65 (5) (2013) 744-755, doi:10.1016/ j.addr.2012.05.007. [139] R. Tian, S. Zhao, G. Liu, H. Chen, L. Ma, H. You, C. Liu, Z. Wang, Construction of lanthanide-doped upconversion nanoparticle-Uelx Europaeus Agglutinin-I b ioconjugates with

f

brightness red emission for u ltrasensitive in v ivo imaging of colorectal tu mor, Bio materials 212 (2019)

oo

64-72, doi:10.1016/j.bio materials.2019.05.010.

[140] F. Li, Y. Du, J. Liu, H. Sun, J. Wang, R. Li, D. Kim, T. Hyeon, D. Ling, Responsive Assembly of Upconversion Nanoparticles for pH-Activated and Near-Infrared-Triggered Photodynamic Therapy of

pr

Deep Tumors, Adv. Mater. 30 (35) (2018) e1802808, doi:10.1002/ad ma.201802808. [141] L. Fan, J. Yang, K.C. Leung, C. Song, Q. Li, Non invasive real-time mon itoring of local drug

e-

release using nano-Au-absorbed self-decomposable SiO2 carriers, Nanoscale 10 (32) (2018) 15332-15338, doi:10.1039/c8nr03782e.

Pr

[142] T. Yang, Y. Tang, L. Liu, X. Lv , Q. Wang, H. Ke, Y. Deng, H. Yang, X. Yang, G. L iu, Y. Zhao, H. Chen, Size-Dependent Ag2S Nanodots for Second Near-Infrared Fluorescence/Photoacoustics doi:10.1021/acsnano.6b07866.

al

Imaging and Simu ltaneous Photothermal Therapy, ACS Nano 11 (2) (2017) 1848-1857, [143] J. Xu, X. Zhou, Z. Gao, Y.Y. Song, P. Sch muki, Visible-Light-Triggered Drug Release fro m

rn

TiO2 Nanotube Arrays: A Controllable Antibacterial Platform, Angew. Chem. Int. Ed. Engl. 55 (2) (2016) 593-597, doi:10.1002/anie.201508710.

Jo u

[144] Y. Qiao, Y. Ping, H. Zhang, B. Zhou, F. Liu, Y. Yu , T. Xie, W. Li, D. Zhong, Y. Zhang, K. Yao, H.A. Santos, M. Zhou, Laser-Activatable CuS Nanodots to Treat Multidrug-Resistant Bacteria and Release Copper Ion to Accelerate Healing of Infected Chronic Nonhealing Wounds, ACS Appl. Mater. Interfaces 11 (4) (2019) 3809-3822, doi:10.1021/acsami.8b21766. [145] C. Scialabba, A. Sciort ino, F. Messina, G. Buscarino, M. Cannas, G. Roscigno, G. Condorelli, G. Cavallaro, G. Giammona, N. Mauro, Highly Ho mogeneous Biotinylated Carbon Nanodots: Red-Emitting Nanoheaters as Theranostic Agents toward Precision Cancer Med icine, A CS Ap pl. Mater. Interfaces 11 (22) (2019) 19854-19866, doi:10.1021/acsami.9b04925. [146] Q. Yang, J. Peng, Y. Xiao, W. Li, L. Tan, X. Xu, Z. Qian, Porous Au@Pt Nanoparticles: Therapeutic

Platform

for

Tu mor

Chemo-Photothermal

Co-Therapy

and

Alleviat ing

Do xorubicin-Induced Oxidative Damage, A CS Appl. Mater. Interfaces 10 (1) (2018) 150 -164, doi:10.1021/acsami.7b14705. [147] T. Yang, H. Ke, Q. Wang, Y.a. Tang, Y. Deng, H. Yang, X. Yang, P. Yang, D. Ling, C. Chen, Y. Zhao, H. Wu, H. Chen, Bifunctional Telluriu m Nanodots for Photo -Induced Synergistic Cancer Therapy, ACS Nano 11 (10) (2017) 10012-10024, doi:10.1021/acsnano.7b04230.

64

Journal Pre-proof [148] W. Cao, Y. Gu , T. Li, H. Xu, Ultra-sensitive ROS-responsive telluriu m-containing poly mers, Chem. Commun. (Camb.) 51 (32) (2015) 7069-7071, doi:10.1039/c5cc01779c . [149] C.G. Dariva, J.F.J. Coelho, A.C. Serra, Near infrared light-triggered nanoparticles using singlet oxygen photocleavage for drug delivery systems, J. Control. Release 294 (2019) 337 -354, doi:10.1016/ j.jconrel.2018.12.042. [150] P. Roschmann, Rad iofrequency penetration and absorption in the human body: limitat ions to high-field who le-body nuclear magnetic resonance imaging, Med. Phys. 14 (6) (1987) 922-931, doi:10.1118/1.595995. [151] S. Dhirender, J.M. Mcmillan, A.V. Kabanov, S.P. Marina, H.E. Gendelman, Bench -to-bedside translation of magnetic nanoparticles, Nanomedicine 9 (4) (2014) 501-516, doi:10.2217/nn m.14.5. [152] C. Dai, C. Wang, R. Hu, H. Lin, Z. Liu, L. Yu, Y. Chen, B. Zhang, Photonic/magnetic

f

hyperthermia -synergistic nanocatalytic cancer therapy enabled by zero -valence iron nanocatalysts,

oo

Biomaterials 219 (2019) 119374, doi:10.1016/j.b io materials.2019.119374.

[153] R.Y. Huang, Y.H. Lin, S.Y. Lin, Y.N. Li, C.S. Chiang, C.W. Chang, Magnetic ternary nanohybrids for nonviral gene delivery of stem cells and applications on cancer therapy, Theranostics 9

pr

(8) (2019) 2411-2423, doi:10.7150/thno.29326.

[154] L. Gloag, M. Mehdipour, D. Chen, R.D. Tilley, J.J. Gooding, Advances in the Application of

e-

Magnetic Nanoparticles for Sensing, Adv. Mater. (2019) 1904385, doi:10.1002/ad ma.201904385. [155] G. Maicas, A.P. Bradley, J.C. Nascimento, I. Reid, G. Carneiro, Pre and post -hoc diagnosis and

Pr

interpretation of malignancy fro m b reast DCE-M RI, Med. Image. Anal. 58 (2019) 101562, doi:10.1016/ j.med ia.2019.101562.

[156] J. Park, K. An, Y. Hwang, J.G. Park, H.J. Noh, J.Y. Kim, J.H. Park, N.M. Hwang, T. Hyeon, doi:10.1038/n mat1251.

al

Ultra-large-scale syntheses of monodisperse nanocrystals, Nat. Mater. 3 (12) (2004) 891 -895,

rn

[157] R.H. Kodama, Magnetic nanoparticles - Condens. Matter, J. Magn. Magn. Mater. 200 (1) (1999) 359-372, doi:10.1016/S0304-8853(99)00347-9

Jo u

[158] S. Sun, H. Zeng, Size-controlled synthesis of magnetite nanoparticles, J. A m. Chem. Soc. 124 (28) (2002) 8204-8205, doi:10.1021/ja026501x. [159] B. Hong, S. Li, Y. Zhang, Y. Du, Ferro magnetic-like behavior of u ltrafine NiO nanocrystallites, J. Magn. Magn. Mater. 277 (3) (2004) 363-367, doi:10.1016/ j.jmmm.2003.11.017 [160] T. Li, Q. Jie, Y. Zhang, Y.X. Wang, X.C. Ni, An Oxide-Diluted Magnetic Semiconductor: Co-Doped

ZnO,

Adv.

Mater.

Res.

652-654

(2013)

585-589,

doi:10.4028/www.scientific.net/amr.652-654.585. [161] A.H. Lu, E.L. Salabas, F. Schuth, Magnetic nanoparticles: synthesis, protection, functionalizat ion, and application, Angew. Chem. Int. Ed. Engl. 46 (8) (2007) 1222-1244, doi:10.1002/anie.200602866. [162] E. To mbacz, R. Turcu, V. Socoliuc, L. Vekas, Magnetic iron oxide nanoparticles: Recent trends in design and synthesis of magnetoresponsive nanosystems, Biochem. Biophys. Res. Co mmun. 468 (3) (2015) 442-453, doi:10.1016/ j.bbrc.2015.08.030. [163] Z. Ferjaoui, E. Jamal Al Dine, A. Ku lmukhamedova, L. Bezdetnaya, C. Soon Chang, R. Schneider, F. Mutelet, D. Mert z, S. Begin-Colin, F. Qu iles, E. Gaffet, H. Alem, Do xorubicin-Loaded Thermoresponsive Superparamagnetic Nanocarrie rs for Controlled Drug Delivery and Magnetic

65

Journal Pre-proof Hyperthermia

Applications, ACS Appl. Mater. Interfaces

11

(34) (2019)

30610-30620,

doi:10.1021/acsami.9b10444. [164] W.E. Strauss, N.V. Dahl, Z. Li, G. Lau, L.F. Allen, Feru mo xyto l versus iron sucrose treatment: a post-hoc analysis of randomized controlled trials in patients with vary ing renal function and iron deficiency anemia, BMC Hematol. 16 (2016) 20, doi:10.1186/s12878-016-0060-x. [165] G.B. Toth, C.G. Varallyay, A. Horvath, M.R. Bashir, P.L. Choyke, H.E. Daldrup -Lin k, E. Dosa, J.P. Finn, S. Gahramanov, M. Harisinghani, I. Macdougall, A. Neuwelt, S.S. Vasanawala, P. A mbady, R. Barajas, J.S. Cetas, J. Ciporen, T.J. DeLoughery, N.D. Doolitt le, R. Fu, J. Grinstead, A.R. Gu imaraes, B.E. Hamilton, X. Li, H.L. McConnell, L.L. Muldoon, G. Nesbit, J.P. Netto, D. Petterson, W.D. Rooney, D. Schwart z, L. Szidonya, E.A. Neuwelt , Current and potential imaging applications of feru mo xytol

for

magnetic

resonance

imaging,

Kidney

Int.

92

(1)

(2017)

47-66,

f

doi:10.1016/ j.kint.2016.12.037.

oo

[166] M.G. Kau l, T. Mu mmert, C. Jung, J. Salamon, A.P. Khandhar, R.M . Ferguson, S.J. Kemp, H. Ittrich, K.M. Krishnan, G. Adam, T. Knopp, In vitro and in vivo comparison of a tailored magnetic particle imaging blood pool tracer with Resovist, Phys. Med. Biol. 62 (9) (2017) 3454-3469,

pr

doi:10.1088/1361-6560/aa5780.

[167] S.N. Tabatabaei, H. Girouard, A.S. Carret, S. Martel, Remote control of the permeability of the

e-

blood-brain barrier by magnetic heating of nanoparticles: A proo f of concept for brain drug delivery, J Control. Release 206 (2015) 49-57, doi:10.1016/ j.jconrel.2015.02.027.

Pr

[168] B.K. Poudel, B. Gupta, T. Ramasamy, R.K. Thapa, S. Pathak, K.T. Oh , J.H. Jeong, H.G. Choi, C.S. Yong, J.O. Kim, PEGylated thermosensitive lip id-coated hollow gold nanoshells for effective combinational chemo-photothermal therapy of pancreatic cancer, Colloids Surf. B Bio interfaces 160

al

(2017) 73-83, doi:10.1016/j.colsurfb.2017.09.010. [169] J. Hu, M .R. Whittaker, J.F. Quinn, T.P. Dav is, Nitric Oxide (NO) Endows Arylamine -Containing

rn

Block Copoly mers with Unique Photoresponsive and Switchable LCST Pro perties, Macro mo lecules 49 (7) (2016) 2741-2749, doi:10.1021/acs.macro mo l.6b00054

Jo u

[170] P. Saint-Cricq, S. Deshayes, J.I. Zink, A.M. Kasko, Magnetic field activated drug delivery using thermodegradable azo-functionalised PEG-coated core-shell

mesoporous silica

nanoparticles,

Nanoscale 7 (31) (2015) 13168-13172, doi:10.1039/c5nr03777h. [171] N.T. Phuoc, J.F. Quinn, A. Anastasaki, M. Rolland, V. Mai, D. Haddleton, M.R. Whittaker, T.P. Davis, Surfactant-free RAFT emu lsion polymerizat ion using a novel biocompatib le thermoresponsive polymer, Polym. Chem. 8 (8) (2017) 1353-1363, doi:10.1039/c6py02158a [172] H. Zhou, F. Zou, K. Koh, J. Lee, Mult ifunctional magnetoplasmonic nanomaterials and their biomed ical

applications,

J.

Bio med.

Nanotechnol.

10

(10)

(2014)

2921-2949,

doi:10.1166/ jbn.2014.1938. [173] J. Bai, J.T. Wang, N. Rubio, A. Protti, H. Heidari, R. Elgogary, P. Southern, W.T. Al -Jamal, J. Sosabowski, A.M. Shah, S. Bals, Q.A. Pan khurst, K.T. Al-Jamal, Triple -Modal Imaging of Magnetically-Targeted Nanocapsules in Solid Tu mours In Vivo, Theranostics 6 (3) (2016) 342 -356, doi:10.7150/thno.11918. [174] H.D. Do, B.M . Couillaud, B.T. Doan, Y. Corv is, N. Mignet, Advances on non -invasive physically triggered nucleic acid delivery fro m nanocarriers, Adv. Drug Deliv. Rev. 138 (2019) 3-17, doi:10.1016/ j.addr.2018.10.006. 66

Journal Pre-proof [175] W. Chen, C.A. Cheng, J.I. Zink, Spatial, Temporal, and Dose Control o f Drug Delivery using Noninvasive

Magnetic

Stimu lation,

ACS

Nano

13

(2)

(2019)

1292-1308,

doi:10.1021/acsnano.8b06655. [176] S.R. Sirsi, M.A. Borden, State-of-the-art materials for u ltrasound-triggered drug delivery, Adv. Drug Deliv. Rev. 72 (2014) 3-14, doi:10.1016/j.addr.2013.12.010. [177] Y.C. Chen, C.F. Ch iang, S.K. Wu, L.F. Chen, W.Y. Hsieh, W.L. Lin, Targeting microbubbles-carrying TGFbeta1 inhibitor co mb ined with ult rasound sonication induce BBB/ BTB disruption to enhance nanomedicine treatment for b rain tu mors, J. Control. Release 211 (2015) 53-62, doi:10.1016/ j.jconrel.2015.05.288. [178] X. Song, L. Feng, C. Liang, K. Yang, Z. Liu, Ultrasound Triggered Tumor Oxygenation with Oxygen-Shuttle Nanoperfluorocarbon to Overco me Hypoxia-Associated Resistance in Cancer

f

Therapies, Nano Lett. 16 (10) (2016) 6145-6153, doi:10.1021/acs.nanolett.6b02365.

oo

[179] C.-Y. Lin, M. Javadi, D.M. Belnap, J.R. Barrow, W.G. Pitt, Ultrasound sensitive eLiposomes containing doxorubicin for drug targeting therapy, Nanomed icine doi:10.1016/ j.nano.2013.06.011.

10 (1) (2014) 67-76,

pr

[180] O. Couture, J. Foley, N.F. Kassell, B. Larrat, J. -F. Aubry, Review of u ltrasound mediated drug delivery for cancer treat ment: updates from pre-clinical studies, Translational. Cancer Res. 3 (5) (2014)

e-

494-511, doi:10.3978/ j.issn.2218-676X.2014.10.01.

[181] P. Cintas, S. Tagliapietra, M . Caporaso, S. Tabasso, G. Cravotto, Enabling technologies built on

Pr

a sonochemical p latform: challenges and opportunities, Ultrason. Sonochem. 25 (2015) 8-16, doi:10.1016/ j.ultsonch.2014.12.004.

[182] A.D. Smith, V.C. Morris, O.A. Levander, Rapid determination of glutathione pero xidase and

al

thioredoxin reductase activities using a 96-well microplate format : co mparison to standard cuvette-based assays, Int. J. Vitam. Nutr. Res. 71 (1) (2001) 87-92, doi:10.1024/0300-9831.71.1.87.

rn

[183] G. Falk, Macro- and Microscale Fabrication by Field Assisted Nanoparticle Assembly - The Challenging Path fro m Science to Engineering, Key Eng. Mater. 507 (2012) 155 -162,

Jo u

doi:10.4028/www.scientific.net/kem.507.155 [184] C. Boehler, C. Kleber, N. Martini, Y. Xie, I. Dryg, T. Stieglit z, U.G. Hofmann, M. Asplund, Actively controlled release of Dexamethasone from neural microelectrodes in a chronic in vivo study, Biomaterials 129 (2017) 176-187, doi:10.1016/j.bio materials.2017.03.019. [185] R. Wadhwa, C.F. Lagenaur, X.T. Cui, Electrochemically controlled release of dexamethasone fro m conducting polymer polypyrro le coated electrode, Journal of Controlled Release 110 (3) (2006) 531-541, doi:10.1016/ j.jconrel.2005.10.027. [186] D. Uppalapati, B.J. Boyd, S. Garg, J. Travas -Sejd ic, D. Svirskis, Conducting polymers with defined

micro- or nanostructures

for drug

delivery, Bio materials

111

( 2016)

149-162,

doi:10.1016/ j.bio materials.2016.09.021. [187] M. Karimi, M . Eslami, P. Sahandi-Zangabad, F. Mirab, N. Farajisafiloo, Z. Shafaei, D. Ghosh, M. Bozo rgomid, F. Dashkhaneh, M.R. Hamb lin, p H-Sensitive stimulus-responsive nanocarriers for targeted delivery of therapeutic agents, Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 8 (5) (2016) 696-716, doi:10.1002/ wnan.1389.

67

Journal Pre-proof [188] Z. Li, Y. Hu, Z. M iao, H. Xu , C. Li, Y. Zhao, Z. Li, M. Chang, Z. Ma, Y. Sun, F. Besenbacher, P. Huang, M. Yu , Dual-Stimu li Responsive Bismuth Nanoraspberries for Mu ltimodal Imaging and Combined Cancer Therapy, Nano Lett. 18 (11) (2018) 6778-6788, doi:10.1021/acs.nanolett.8b02639. [189] W. Huang, H. Zhao, J. Wan, Y. Zhou, Q. Xu, Y. Zhao, X. Yang, L. Gan, pH - and photothermal-driven mult istage delivery nanoplatform for overcoming cancer drug resistance, Theranostics 9 (13) (2019) 3825-3839, doi:10.7150/thno.33958. [190] R. Cheng, F. Meng, C. Deng, H.A. Klok, Z. Zhong, Dual and mu lti -stimuli responsive polymeric nanoparticles for programmed site-specific d rug delivery, Bio materials 34 (14) (2013) 3647-3657, doi:10.1016/ j.bio materials.2013.01.084. [191] J.T. Hart mann, H.P. Lipp, To xicity of platinu m co mpounds, Expert Opin. Pharmacother. 4 (6) (2003) 889-901, doi:10.1517/ 14656566.4.6.889. resistance

and

induced

side

effects,

Cancers

(Basel)

3

oo

drug

f

[192] A.M. Florea, D. Busselberg, Cisplatin as an anti-tumor drug: cellu lar mechanisms of activity, doi:10.3390/cancers3011351.

(1)

(2011)

1351-1371,

[193] J. Xu, Y. Kuang, R. Lv, P. Yang, C. Li, H. Bi, B. Liu, D. Yang, Y. Dai, S. Gai, F. He, B. Xing, J.

pr

Lin, Charge convertibility and near infrared photon co -enhanced cisplatin chemotherapy based on upconversion nanoplatform, Biomaterials 130 (2017) 42-55, doi:10.1016/ j.b io materials.2017.03.041.

e-

[194] C. Qian, J. Yu, Y. Chen, Q. Hu, X. Xiao, W. Sun, C. Wang, P. Feng, Q.-D. Shen, Z. Gu, Light-Activated Hypoxia-Responsive Nanocarriers for Enhanced Anticancer Therapy, Adv. Mater. 28

Pr

(17) (2016) 3313-3320, doi:10.1002/ad ma.201505869.

[195] D. Chen, Y. Tang, J. Zhu, J. Zhang, X. Song, W. Wang, J. Shao, W. Huang, P. Chen, X. Dong, Photothermal-p H-hypoxia responsive multifunctional nanoplatform for cancer photo-chemo therapy negligib le

skin

phototoxicity,

Bio materials

al

with

221

(2019)

119422,

doi:10.1016/ j.bio materials.2019.119422.

rn

[196] A. Raza, T. Rasheed, F. Nabeel, U. Hayat, M. Bilal, H.M.N. Iqbal, Endogenous and Exogenous Stimu li-Responsive Drug Delivery Systems for Programmed Site-Specific Release, Molecules 24 (6)

Jo u

(2019) 1117, doi:10.3390/ mo lecules24061117. [197] S. Mura, J. Nico las, P. Couvreur, St imuli-responsive nanocarriers for drug delivery, Nat. Mater. 12 (11) (2013) 991-1003, doi:10.1038/n mat3776. [198] G. Yang, S.Z.F. Phua, A.K. Bindra, Y. Zhao, Degradability and Clearance of Inorganic Nanoparticles

for

Bio med ical

Applications,

Adv.

Mater.

31

(10)

(2019)

1805730,

doi:10.1002/ad ma.201805730. [199] Z. Zhao, A. Ukidve, V. Krishnan, S. Mitragotri, Effect of physicochemical and surface properties on

in

vivo

fate

of

d rug

nanocarriers,

Adv.

Drug

Deliv.

Rev.

143

(2019)

3-21,

doi:10.1016/ j.addr.2019.01.002. [200] A. Nel, T. Xia, L. Madler, N. Li, To xic potential of materials at the nanolevel, Science 311 (5761) (2006) 622-627, doi:10.1126/science.1114397. [201] J. Liu, M . Yu , C. Zhou, S. Yang, X. Ning, J. Zheng, Passive tumor targeting of renal -clearable lu minescent gold nanoparticles: long tumor retention and fast normal t issue clearance, J. A m. Chem. Soc. 135 (13) (2013) 4978-4981, doi:10.1021/ja401612x

68

Journal Pre-proof [202] Q. Wang, S. Wang, X. Hu, F. Li, D. Ling, Controlled synthesis and assembly of u ltra -s mall nanoclusters

for

bio medical

applications,

Bio mater.

Sci.

(7)

(2019)

480 -489,

doi:10.1039/ C8BM 01200H [203] X. Hu, J. Sun, F. Li, R. Li, J. Wu, J. He, N. Wang, J. Liu, S. Wang, F. Zhou, X. Sun, D. Kim, T. Hyeon, D. Ling, Renal-Clearable Hollow Bis muth Subcarbonate Nanotubes for Tumor Targeted Co mputed Tomography Imaging and Chemoradiotherapy, Nano Lett. 18 (2) (2018) 1196-1204, doi:10.1021/acs.nanolett.7b04741. [204] Q. Wei, C. Yao, X. Ma, J. Ji, Q. Yue, Z. Bo, M . Fei, D. Ling, Z. Hong, T. Mei, High-Efficient Clearable Nanoparticles for Mult i-Modal Imaging and Image-Gu ided Cancer Therapy, Adv. Funct. Mater. 28 (2017) 1704634, doi:10.1002/adfm.201704634. [205] M.L. Etheridge, S.A. Campbell, A.G. Erd man, C.L. Haynes, S.M . Wolf, J. McCullough, The big

oo

Nanomedicine 9 (1) (2013) 1-14, doi:10.1016/ j.nano.2012.05.013.

f

picture on nanomedicine: the state of investigational and approved nanomedicine products, [206] L.H. Lindner, M. Hossann, M. Vogeser, N. Teichert, K. Wachholz, H. Eib l, W. Hiddemann, R.D. Issels, Dual role of hexadecylphosphocholine (miltefosine) in thermosensitive liposomes: active mediator o f drug

release, J

doi:10.1016/ j.jconrel.2007.10.009.

Control Release 125 (2)

pr

ingredient and

(2008) 112 -120,

e-

[207] D. Liu, F. Yang, F. Xiong, N. Gu, The Smart Drug Delivery System and Its Clinical Potential, Theranostics 6 (9) (2016) 1306-1323, doi:10.7150/thno.14858.

Pr

[208] P. Rivera Gil, D. Huhn, L.L. del Mercato, D. Sasse, W.J. Parak, Nanopharmacy: Inorganic nanoscale devices as vectors and active compounds, Pharmacol Res 62 (2) (2010) 115 -125, doi:10.1016/ j.phrs.2010.01.009.

al

[209] J.A. Schwartz, A.M. Shetty, R.E. Price, R.J. Stafford, J.C. Wang, R.K. Uthamanthil, K. Pham, R.J. McNichols, C.L. Co leman, J.D. Payne, Feasibility study of particle -assisted laser ablat ion of brain in

orthotopic

canine

model,

rn

tumors

Cancer

Res

69

(4)

(2009)

1659-1667,

doi:10.1158/0008-5472.Can-08-2535.

Jo u

[210] S.A. Shaffer, C. Baker-Lee, J. Kennedy, M.S. Lai, P. de Vries, K. Buhler, J.W. Singer, In vitro and in vivo metabolism of paclitaxel poliglu mex: identificat ion of metabolites and active proteases, Cancer Chemother Pharmacol 59 (4) (2007) 537-548, doi:10.1007/s00280-006-0296-4.

Credit author statement Fangyuan Li: Conceptualization, Writing - Original Draft, Writing - Review & Editing. Yu Qin: Writing - Original Draft, Visualization, Review & Editing. Jiyoung Lee: Writing - Original Draft, Visualization, Review & Editing. Hongwei Liao: Writing - Original Draft, Writing - Review & Editing. Nan Wang: Writing - Original Draft, Writing - Review & Editing. 69

Journal Pre-proof Thomas P. Davis: Supervision, Writing - Review & Editing. Ruirui Qiao: Supervision, Writing - Review & Editing. Daishun Ling: Supervision, Writing - Review & Editing, Project administration, Funding acquisition.

e-

pr

oo

f

Graphical abstract

Pr

The current state-of-the-art technologies for nano-assemblies construction, and their

al

applications in remotely controlled nano-assembly-based DDSs.

rn

Highlights

• Stimuli-responsive nano-assemblies are promising drug delivery systems for

Jo u

controlled drug release

• Nano-assemblies responsive to exogenous stimuli are employed for remotely controlled drug delivery

• The properties of the nano-assembly-based drug delivery systems are dependent on stimuli-triggered structural transition • Bio-cleanable stimuli-responsive nano-assemblies hold great potential for clinical translation.

70

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Figure 20

Figure 21

Figure 22