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The combination of stimuli-activable prodrug based chemotherapy and photodynamic therapy (PDT) has attracted increasing attention. Recent studies have verified the effectiveness of this strategy in the treatment of multiple aggressive cancers. However, in such combination, the stimuli-responsive chemotherapy and PDT have their own problems that need to be overcome. The uneven distribution of endogenous stimuli within tumor tissues makes it difficult for prodrug to be completely activated. And the inadequate tissue penetration depth of external light results in low efficiency of PDT. Aiming at these two bottlenecks, we designed a biocompatible dextran based - multi-component nanomedicine (PCL-NPs) that integrate a chemiluminescence agent luminol, a photosensitizer chlorine e6 (Ce6), and a reactive oxygen species (ROS)-activable thioketal-based paclitaxel (PTX) prodrug. The presence of overexpressed hydrogen peroxide (H2O2) inside tumor oxidizes the luminol moiety to generate in-situ light for PDT through chemiluminescence resonance energy transfer (CRET). The singlet oxygen (1O2) produced in this process not only directly kills tumor cells but also amplifies oxidative stress to accelerate the activation of PTX prodrug. We propose that the PCL-NPs have great therapeutic potential by simultaneously enhancing chemotherapy and PDT in a combination therapy.

Prodrugs are chemically modified drug molecules that are inactive before administration. After administration, they are converted in situ to parent drugs and induce the mechanism of action. The development of prodrugs has upgraded conventional drug treatments in terms of bioavailability, targeting, and reduced side effects. Especially in cancer therapy, the application of prodrugs has achieved substantial therapeutic effects. From serendipitous discovery in the early stage to functional design with pertinence nowadays, the importance of prodrugs in drug design is self-evident. At present, studying stimuli-responsive activation mechanisms, regulating the stimuli intensity in vivo, and designing nanoscale prodrug formulations are the major strategies to promote the development of prodrugs. In this review, we provide an outlook of recent cutting-edge studies on stimuli-responsive prodrug nanosystems from these three aspects. We also discuss prospects and challenges in the future development of such prodrugs. National Research Foundation (NRF) Submitted/Accepted version This work was supported by the start-up fund (BS2021001) from Maoming People’s Hospital, the Guangdong Medical Science and Technology Research Fund (A2021213), the Programs Supported by Tianjin Key Laboratory of Biomedical Materials, the National Natural Science Foundation of China (32101065), and the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-03).

Integrating multimodality bioimaging and multiple stimuli-responsive controlled drug release properties into one single nanosystem for therapeutic application is highly desirable but still remains a challenge. Herein, we coated a hollow mesoporous silica shell on to upconversion nanoparticles (UCNPs) and conjugated pillarene-based supramolecular valves on to surface of UCNPs@hm-SiO2 using amine-coumarin phototriggers to obtain the multifunctional nanoparticles, UCNPs@hm-SiO2-Cou-Cys-DOX/WP[5]. Benefiting from the core-shell structured UCNPs, the UCNPs@hm-SiO2-Cou-Cys-DOX/WP[5] can serve as efficient contrast agents for upconversion luminescence and T1-weighted magnetic resonance imaging in vitro/in vivo. More importantly, depending on exquisitely designed supramolecular valves, UCNPs@hm-SiO2-Cou-Cys-DOX/WP[5] can realize zero-premature release under normal physiological conditions (pH 7.4), which produces minimal damage to normal tissue, whereas this nanosystem can respond to several disease-related signals, including acid (most cancers), alkali (metabolic alkalosis), and Zn2+ (Alzheimer's disease), along with two external stimuli, including near-infrared (NIR) light and reductive electrical potential, via altering the spatial structure of pseudorotaxanes, disassembling the molecular stalks, or undergoing photochemical reactions, ultimately resulting in opening of the gatekeepers and release of encapsulated drugs. The multifunctional UCNP-based nanoparticles were endowed with such quintuple stimuli-responsive controlled release characteristics. Specifically, in anticancer application, the rational utilization of the two of them, acid and NIR light, could regulate the release amount and rate of DOX from UCNPs@hm-SiO2-Cou-Cys-DOX/WP[5], accelerate the accumulation of DOX in cell nuclei, and thereby promote the cancer cell apoptosis, indicating that the nanomaterials have promising application in cancer treatment. This study provides a novel design strategy for constructing multifunctional UCNP-based nanoparticles with multiple stimuli-responsive drug release features, which have great potential in diagnosis and therapy of relevant diseases as theranostic nanomedicines.

Integrating multimodality bioimaging and multiple stimuli-responsive controlled drug release properties into one single nanosystem for therapeutic application is highly desirable but still remains a challenge. Herein, we coated a hollow mesoporous silica shell on to upconversion nanoparticles (UCNPs) and conjugated pillarene-based supramolecular valves on to surface of UCNPs@hm-SiO

A superhydrophobic, self-healing anti-corrosion coating was prepared by in-situ growth of tungstate corrosion inhibitor intercalated layer double hydroxides (LDHs) conversion film on the AZ31B magnesium alloy and then post-sealing a hydrophobic polymer layer of ureido crosslinked polydimethylsiloxane (U-PDMS) with laurate modified LDHs power (La-LDH) on the surface. The coverage of the dense, water-repellent top layer could suppress the penetration of electrolyte into the bottom LDHs layer and preserve the intercalated tungstate inhibitor from being wasted by ion-exchange at the very beginning of immersion. The anti-corrosion performance provided by the composite film was assessed by multiple methods including, potentiodynamic polarization, open circuit potential (OCP), electrochemical impedance spectroscopy (EIS), immersion test and scanning vibrating electrode technique (SVET). The results indicate that compared to LDHs coating, the superhydrophobic composite coating shows longer term protection and faster self-healing effect, which is of great significance to expand the potential applications of magnesium alloys.

We constructed triple-stimuli-responsive nanocontainers (T-SRNs), consisting of mesoporous silica nanoparticles for accommodating cargoes and bistable [2]pseudorotaxanes for regulating cargoes and realizing controlled release. T-SRNs eliminate premature leakage of model cargoes under neutral solution conditions by the formation of complexes of water-soluble carboxylate-substituted pillar[5]arenes (WP5) with 1,6-hexanediammonium (HDA) recognition stations to block pore orifices. After exposure to acid, alkali pH or Zn2+ environments, T-SRNs release encapsulated cargoes promptly, which can be attributed to the dethreading of WP5 from HDA sites by different approaches and the lack of stoppers. The unique acid/alkali/Zn2+-responsive controlled release characteristic mean that T-SRNs have potential in some application fields. Herein, MTT assays and in vitro release of doxorubicin from T-SRNs demonstrate that T-SRNs can serve as promising targeted drug delivery vehicles.

Stretchable and autonomously self-healable elastomers with wide-ranging tunable mechanical properties have attracted increasing attention in various industries. To date, it continues to be a huge challenge to synthesize self-healing elastomers integrating extreme stretchability, relatively high mechanical modulus, and autonomous and rapid self-healing capability. Herein, we propose a novel covalent/supramolecular hybrid construction strategy, in which the covalent cross-links are responsible for providing high modulus and elasticity, while supramolecular cross-links realize extreme stretchability and rapid self-healing under room temperature depending on the ultrafast exchange kinetics of metal–ligand motifs and multicoordination modes. The representative polyurea hybrid elastomer, CSH-PPG-Zn-0.25, can be stretched more than 180× its original length with the highest Young’s modulus (1.78 ± 0.08 MPa) among reported ultrastretchable materials. CSH-PPG-Zn-0.25 can fully restore mechanical properties of compl...

In recent years, the unprecedented advances of biomedical nanotechnology have spurred the development of drug delivery systems (DDSs) based on multifarious nanomaterials in disease treatment and diagnostic purposes, which simultaneously boost the therapeutic outcome and circumvent the side effects. Among these, mesoporous silica nanoparticles (MSNs) are acknowledged as one of the most promising candidates for cargo delivery. Their remarkable intrinsic features, including size and porosity tunability, large surface area, high pore volume, versatile surface functionality as well as biocompatibility, have arouse tremendous research of MSNs as multifunctional delivery platforms. In particular, intelligent MSNs-based controlled delivery systems with stimuli-responsive characteristics hold great promise in personalized precision medicine in clinical applications. Notably, benefiting from the tunable pore size and diversified surface chemistry, MSNs-based systems can transport a variety of therapeutic agents such as small-molecule drug, gene, peptide, as well as protein, which have tremendous potential to treat diverse types of diseases, including carcinoma, bacterial infections (infectious diseases), diabetes, bone disorders, Alzheimer’s disease, etc. In this review, a brief overview of MSNs and their features, together with the discussions on engineering of stimuli-responsive MSNs-based systems for on-demand payload delivery is presented. Further, the application of the state-of-the-art MSNs-based delivery systems in multifarious disease therapeutics (not limited to carcinoma) with a particular focus on recent studies is summarized. Finally, the clinical translation issues encountered by these delivery platforms and their possible solutions together with future perspectives of MSN-based systems in clinics are also mentioned.

Motivated by the demand for anticorrosion coating with high performance to improve the reliability and sustainability of metallic materials in corrosive environments, smart nanocontainers that can confer active protection have been highly desirable. The combination of nanocontainer researches and anticorrosion technology bolsters the development of “smart” anticorrosion coatings. Due to the participation of nanocontainers, healing agents undergo stimulus-responsive release to fulfill repairing function. Integrating both passive barrier function and self-healing property, this burgeoning technology is more reliable in proving long-term protection. We summarize the working mechanism of these coatings based on different types of nanocontainer scaffold and the triggers. The characterization methods of nanocontainer-based anticorrosion coatings are also discussed.

Developing artificial systems to mimic the emergence of chirality is of vital importance in better understanding the mysterious origin of natural homochirality and guiding the design of advanced chiroptical materials. Herein, we present a DNA-inspired control over the emergence of supramolecular nanoscale chirality in multiple hydrogen-bonded self-assemblies. N-Terminated aromatic amino acids bearing serine and aromatic domains could self-assemble into lamellar microsheets without nanoscale chirality, ascribed to their pronounced molecular stacking preference on two-dimensional orientations. Significantly, when achiral bipyridine-, melamine-, and imidazole-based molecular binders that could potentially form hydrogen-bonded complexes with these aromatic amino acids were introduced, the induced chiral nanostructures from the resulting coassemblies were observed. Melamine and its derivatives presented an excellent capability to generate ordered supramolecular structures and induce the nanoscale chirality. Assisted by the key duplex hydrogen bonds between the melamine core and serine segments, chiral nanotubes and ribbons were obtained. This study reveals that multiple hydrogen bonds are the prerequisite for inducing the emergence of chiral nanostructures from integrated coassemblies.

Redox-triggered smart nanocontainers, RTSNs 1, assembled by installing supramolecular switches onto the exterior surface of mesoporous silica nanoparticles, were successfully synthesized. The reversible transition upon redox stimuli from self-complexation to self-dissociation of supramolecular switches, which are in the form of β-cyclodextrin monofunctionalized with a ferrocene moiety, realizes switch behavior and regulates the release of p-coumaric acid (CA) encapsulated in mesoporous silica nanoparticles. Based on these facts, a bi-layered nanocomposite coating was designed and coated on the surface of AA2024 by successive deposition of a Ce(IV)-doped ZrO2–SiO2 sol–gel coating and an RTSNs 1 incorporated ZrO2–SiO2 coating. The bi-layered nanocomposite coating shows high barrier performance, effectively delaying the corrosion process occurring on the metallic surface in 0.5 M NaCl solution for 20 days. Once the bi-layered nanocomposite coating suffers local damage, Ce(IV) salt meets with RTSNs 1 in the scratched area and thus open the supramolecular switches, resulting in the release of the organic corrosion inhibitors, CA molecules. In the meantime, Ce(IV) salt is reduced to the inorganic corrosion inhibitor, Ce(III) salt. The combination of CA and Ce(III) produces a synergistic inhibition effect, which rapidly repairs the damaged surface and provides durable self-healing functionality.

We demonstrate for the first time how to assemble mechanized hollow zirconia nanospheres (MHzNs), consisting of hollow mesoporous zirconia nanospheres (HMZNs) as nanoscaffolds and supramolecular switches anchored on the exterior surface of HMZNs. The remarkable advantage of substitution of HMZNs for conventional mesoporous silica nanoscaffolds is that HMZNs can suffer the hot alkaline reaction environment, which provides a novel strategy for functionalization and thus achieve dual pH-mediated controlled release functions by simple and practicable assembly procedure. Under neutral solution, cucurbituril[7] (CB[7]) macrocycles complexed with propanone bis(2-aminoethyl)ketal (PBAEK) to form [2]pseudorotaxanes as supramolecular switches, blocking the pore orifices and preventing the undesirable leakage of cargoes. When solution pH was adjusted to alkaline range, CB[7] macrocycles, acting as caps, disassociated from PBAEK stalks and opened the switches due to the dramatic decrease of ion-dipole interactions. While under acidic conditions, PBAEK stalks were broken on account of the cleavage of ketal groups, resulting in the collapse of supramolecular switches and subsequent release of encapsulated cargoes. MHzNs owning dual pH-mediated controlled release characteristic are expected to apply in many fields. In this work, the feasibility of doxorubicin (DOX)-loaded MHzNs as targeted drug delivery systems was evaluated. In vitro cellular studies demonstrate that DOX-loaded MHzNs can be easily taken up by SMMC-7721 cells, can rapidly release DOX intracellularly, and can enhance cytotoxicity against tumor cells, proving their potential for chemotherapy.

Advanced rechargeable lithium-based batteries have a profound effect on our global society and polymer materials are one of the key components of these batteries. The key roles of polymers applied in battery technology are presented in terms of binders, package coatings, separators, and electrolytes. However, the loathsomely structural changes during repeated charge/discharge processes result in the mechanical fracture problems of polymers inside batteries, which significantly reduce the cycling lifetimes. The use of intrinsic self-healing polymers as substitutes is one of the most favored strategies for reviving lithium-based batteries since self-healing polymers spontaneously eliminate the mechanical cracks or damages and result in greatly enhanced electrochemical performances. In this review, we first introduce the advances and working mechanism of intrinsic self-healing polymers. Then, we discuss the opportunities and challenges in the development of advanced lithium-based batteries with Si, Li-metal, S electrodes, and polymer electrolytes, respectively, and summarize the up-to-date key progress in intrinsic self-healing polymers for solving the above-mentioned challenges. Finally, we propose some designing principles of desired intrinsic self-healing polymers from the perspectives of basic structures, ionic conductivities, mechanical properties, chemical interactions, and the self-healing capabilities.

The colonization of microbe on the material surface causes serious damage to the fields of biomedicine, water purification, and biosensors, and therefore versatile and biocompatible anti-biofouling coatings are highly demanded. Here, we fabricated a dual-functional (fouling-resist and antibacterial properties) anti-biofouling self-healing coating (DASC) with the triplex-crosslinked network (the covalent bonds, hydrogen bonds, and ionic interactions), which could be coated on 316L stainless steel substrate and demonstrated strong adhesive strength. The DASC-15 (the quaternary ammonium compounds accounts for 15 mol%) could inhibit the adhesion of biofouling due to its hydroxyethyl acrylate (HEA) and poly(ethylene glycol) methyl ether acrylate (PEGA480) units, and its anti-protein adhesion efficiency reached 90%. The presence of the quaternary ammonium compounds cations endowed the DASC-15 with excellent broad-spectrum antibacterial property, and the killing efficiency against Staphylococcus aureus and Escherichia coli was approximately 99.9%. Moreover, The DASC-15 could be repaired within 15 min under ambient condition after being scratched. The mechanical property restored to 93% of its original condition, which was derived from the destruction and recombination of the supramolecular non-covalent bonds. More prominently, larger scratches with the width of 200 μm could be repaired and the anti-biofouling property remained at the humidity of 90%. The coating is promising for biomaterial due to its strong metal adhesion, good biocompatibility, excellent anti-biofouling and outstanding self-healing properties.

The chemotherapy combined with gene therapy has emerged as a promising strategy for cancer therapy because of enhanced anticancer efficacy. To this end, we constructed a novel UV-light cross-linked and pH de-cross-linked coumarin-decorated cationic copolymer functionalized mesoporous silica nanoparticles (MSN) for co-delivery of chemotherapeutic agent 5-FU and tumor suppresser p53 gene. The multifunctional MSN were modified with poly(glycidyl methacrylate)-b-poly(2-(dimethylamino)ethyl methacrylate) (PGMA-b-PDMAEMA) via two sequential surface-initiated atom transfer radical polymerization (ATRP), followed by ring-opening of epoxy groups with ethanediamine and covalent conjugation with coumarin moieties via acid-liable cis-aconityl bonds. The in vitro drug release results indicated that the premature release was negligible at physiological pH when coumarin moieties on the MSN-g-PCAAMC-b-PDMAEMA surface underwent UV-light induced photo-dimerization (cross-linking), while the release of embedded drugs was accelerated under acidic conditions, which was attributed to the hydrolytic cleavage of cis-aconityl bonds (de-crosslinking). In addition to small-molecule drug, the established MSN-g-PCAAMC-b-PDMAEMA also could carry p53 gene in outer cationic copolymers, and the formed complex exhibited good gene transfection activity. Interestingly, coumarin moieties themselves could emit blue fluorescence, which was used to track the cellular uptake of the nanocarriers without the need of additional fluorescence probes. Importantly, the cytotoxicity and cell apoptosis assays confirmed that co-delivery of 5-FU and p53 gene by the cross-linked MSN-g-PCAAMC-b-PDMAEMA@5-FU/p53 induced enhanced chemotherapeutic efficacy as compared to 5-FU delivery alone. In conclusion, these results suggested that the constructed stimuli-responsive co-delivery system may hold the promise for cancer therapeutic application.

Novel quadruple stimuli-responsive mechanized silica nanoparticles were constructed by installation of supramolecular nanovalves onto the exterior surface of mesoporous silica nanoparticles. The release of cargo molecules is triggered by acid/Zn2+ /alkali/reduction potential stimuli. This has potential application in the development of drug delivery systems or construction of smart anticorrosion coatings.

Benefiting the major advantages such as high strength to weight ratio and good formability, magnesium alloy, as a significant light alloy, has shown great potential in modern machine manufacturing field. Unfortunately, limited by their poor corrosion resistance and fast degradation rate, magnesium alloy materials face predicament in stability and durability. Considering that the degradation rate of magnesium alloy is very quick, the repairing speed should also be fast enough to overtake the corrosion process. Hence, sensitive, rapid responsiveness and fast repair process is necessary for magnesium alloy protection. Electrochemical potential was chosen as indicator to monitor the corrosion process: It decreases as soon as the corrosion took place, and it only declined with corrosion reaction. This character guarantees the sensitivity of self-healing coating based on electrochemical potential mechanism to sense the very beginning of corrosion reaction. Disulfide bond unit was frequently introduced into controlled release systems for redox-responsiveness due to that they could easily be reduced and cleaved into thiol groups. Inside human body, there exists abundant glutathione (GSH) in the cytosol. This reducing substance could realize rapid cleavage of disulfide bonds. According to previous literatures, the half-cell potential of GSSG/GSH was -0.26 V, while for magnesium alloy, their corrosion potential is much lower. Therefore, it is expected that the redox reactions during corrosion of magnesium alloy would have the same effect in cleaving disulfide bond as GSH. Following this biomimetic idea, corrosion environment combined with disulfide could realize redox-responsive self-healing agent release, composing the most dependable self-healing mechanism. Herein, we report a sensitive, intelligent anticorrosion sol-gel pre-treatment coating based on redox-responsive motif. As key component, self-healing agent, the inhibitor molecules benzotriazole (BTA) was located inside mesoporous silica materials, sealed by supramolecular complex gate. Composed by novel macrocyclic molecules, water soluble pillar[5]arenes (WP5) and pyridine cation derivative molecules (G), the formation of supramolecular complex is driven by electrostatic force and hydrophobic function. Disulfide bonds were used as linker connecting surface of mesoporous silica nanospheres and the “gate” molecules. To shorten the travel path of inhibitor molecules, we added Fe3O4 nanoparticles inside mesoporous silica layer to fabricate magnetic intelligent nanocontainers. To our knowledge, the magnetic properties have been widely used for controlling the location of materials. Therefore, under the effect of external magnetic field, the magnetic nanocontainer with BTA wrapped inside could be enriched to coating-metal interface. Through shortening the travel path, the inhibitor molecules could reach the corroded areas in minimal time, further accelerating repairing speed. Through evaluations by in-situ scanning kelvin probe technique (SKP), the reported coating exhibit the rapid self-healing functionality, give the timely feedback and maintain the reliable long-term protection of magnesium alloy. 15 μL of 0.05 M NaCl electrolyte was covered on artificial defect (deep into the alloy layer, simulating the coating deterioration at the beginning of corrosion) and NiCr SKP probe was positioned 100μm above the sample surface. Through non-destructive, in-situ measurement of electrode potential at metal surface, a function of the potential over time was recorded (Figure 1B). At the beginning of immersion, the potential at defect site remains level, at the corrosion potential of AZ31B (-1.5 V), indicating that the contact between metal and electrolyte leads to active corrosion in all the samples. After four hours of immersion, the corrosion potential of doped sample rockets to -1.05 V, entering into the passivation range, while for undoped sample, it did not display self-healing function. This is the first time that precise control over location of repair factor inside coatings is achieved. Figure 1

The self-complexation of mono-benzimidazole functionalized β-cyclodextrins was investigated. The unique molecular structure employed as supramolecular nanovalves were installed on the external surface of mesoporous silica to assemble mechanized silica nanoparticles, which showed pH-triggered release property.

Cucurbit[6]uril-based reversible bistable [2]pseudorotaxanes were designed, synthesized and installed on the surface of mesoporous silica nanoparticles as supramolecular nanovalves. The assembled mechanized silica nanoparticles realize the multistage pH-controlled release of benzotriazole and the potential for reutilization.

Luminescent graphene quantum dots (GQDs) have been capped onto the nanopores of mesoporous silica nanoparticles (MSNs) through an acid-cleavable acetal bond. Herein, the GQDs behave as dual-purpose entities that act as capping agents and also exhibit excellent photoluminescence property.