Occurrence of Chiral Nanostructures Induced by Multiple Hydrogen Bonds.

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.

Quadruple Stimuli-Responsive Mechanized Silica Nanoparticles: A Promising Multifunctional Nanomaterial for Diverse Applications.

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.

Recent Advances in Stimuli-Responsive Release Function Drug Delivery Systems for Tumor Treatment.

Benefiting from the development of nanotechnology, drug delivery systems (DDSs) with stimuli-responsive controlled release function show great potential in clinical anti-tumor applications. By using a DDS, the harsh side effects of traditional anti-cancer drug treatments and damage to normal tissues and organs can be avoided to the greatest extent. An ideal DDS must firstly meet bio-safety standards and secondarily the efficiency-related demands of a large drug payload and controlled release function. This review highlights recent research progress on DDSs with stimuli-responsive characteristics. The first section briefly reviews the nanoscale scaffolds of DDSs, including mesoporous nanoparticles, polymers, metal-organic frameworks (MOFs), quantum dots (QDs) and carbon nanotubes (CNTs). The second section presents the main types of stimuli-responsive mechanisms and classifies these into two categories: intrinsic (pH, redox state, biomolecules) and extrinsic (temperature, light irradiation, magnetic field and ultrasound) ones. Clinical applications of DDS, future challenges and perspectives are also mentioned.

Dextran-based micelles for combinational chemo-photodynamic therapy of tumors via in vivo chemiluminescence.

Natural polysaccharides, represented by dextran, chitosan, and hyaluronic acid, are widely approved for use as pharmaceutical excipients and are important carrier materials for the design of advanced drug delivery systems, particularly in the field of anticancer drug delivery. 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.

Biofilm microenvironment triggered self-enhancing photodynamic immunomodulatory microneedle for diabetic wound therapy.

The treatment of diabetic wounds faces enormous challenges due to complex wound environments, such as infected biofilms, excessive inflammation, and impaired angiogenesis. The critical role of the microenvironment in the chronic diabetic wounds has not been addressed for therapeutic development. Herein, we develop a microneedle (MN) bandage functionalized with dopamine-coated hybrid nanoparticles containing selenium and chlorin e6 (SeC@PA), which is capable of the dual-directional regulation of reactive species (RS) generation, including reactive oxygen species (ROS) and reactive nitrogen species (RNS), in response to the wound microenvironment. The SeC@PA MN bandage can disrupt barriers in wound coverings for efficient SeC@PA delivery. SeC@PA not only depletes endogenous glutathione (GSH) to enhance the anti-biofilm effect of RS, but also degrades GSH in biofilms through cascade reactions to generate more lethal RS for biofilm eradication. SeC@PA acts as an RS scavenger in wound beds with low GSH levels, exerting an anti-inflammatory effect. SeC@PA also promotes the M2-phenotype polarization of macrophages, accelerating wound healing. This self-enhanced, catabolic and dynamic therapy, activated by the wound microenvironment, provides an approach for treating chronic wounds.

NIR-dye bridged human serum albumin reassemblies for effective photothermal therapy of tumor.

Human serum albumin (HSA) based drug delivery platforms that feature desirable biocompatibility and pharmacokinetic property are rapidly developed for tumor-targeted drug delivery. Even though various HSA-based platforms have been established, it is still of great significance to develop more efficient preparation technology to broaden the therapeutic applications of HSA-based nano-carriers. Here we report a bridging strategy that unfastens HSA to polypeptide chains and subsequently crosslinks these chains by a bridge-like molecule (BPY-Mal2) to afford the HSA reassemblies formulation (BPY@HSA) with enhanced loading capacity, endowing the BPY@HSA with uniformed size, high photothermal efficacy, and favorable therapeutic features. Both in vitro and in vivo studies demonstrate that the BPY@HSA presents higher delivery efficacy and more prominent photothermal therapeutic performance than that of the conventionally prepared formulation. The feasibility in preparation, stability, high photothermal conversion efficacy, and biocompatibility of BPY@HSA may facilitate it as an efficient photothermal agents (PTAs) for tumor photothermal therapy (PTT). This work provides a facile strategy to enhance the loading capacity of HSA-based crosslinking platforms in order to improve delivery efficacy and therapeutic effect.

Emerging Strategies in Stimuli-Responsive Prodrug Nanosystems for Cancer 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.

UV-light cross-linked and pH de-cross-linked coumarin-decorated cationic copolymer grafted mesoporous silica nanoparticles for drug and gene co-delivery in vitro.

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.

Supramolecular Valves Functionalized Rattle-Structured UCNPs@hm-SiO2 Nanoparticles with Controlled Drug Release Triggered by Quintuple Stimuli and Dual-Modality Imaging Functions: A Potential Theranostic Nanomedicine.

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.

Design and Fabrication of a Novel Stimulus-Feedback Anticorrosion Coating Featured by Rapid Self-Healing Functionality for the Protection of Magnesium Alloy.

Corrosion potential stimulus-responsive smart nanocontainers (CP-SNCs) are designed and synthesized based on the installation of the supramolecular assemblies (bipyridinium ⊂ water-soluble pillar[5]arenes) onto the exterior surface of magnetic nanovehicles (Fe3O4@mSiO2), linked by disulfide linkers. The supramolecular assemblies with high binding affinity as gatekeepers effectively block the encapsulated organic corrosion inhibitor, 8-hydroxyquinoline (8-HQ), within the mesopores of Fe3O4@mSiO2. When the corrosion potential of the magnesium alloy (-1.5 V vs SHE) is exerted, 8-HQ is released instantly because of the cleavage of disulfide linkers and the removal of the supramolecular assemblies. CP-SNCs were incorporated into the hybrid organic-inorganic sol-gel coating to construct a corrosion potential stimulus-feedback anticorrosion coating (CP-SFAC) that was then deposited on the magnesium alloy, AZ31B. With the aid of a magnetic field, CP-SNCs were gathered in the proximity of the surface of AZ31B. CP-SFAC showed a satisfactory anticorrosion performance, more importantly, through the evaluation of microzone electrochemical techniques. CP-SFAC presented the rapid self-healing functionality when the localized corrosion occurred. Shortening the distance between CP-SNCs and the surface of AZ31B enhances the availability of the incorporated CP-SNCs and makes most of the CP-SNCs to timely respond to the corrosion potential stimulus and facilitates the formation of a compact molecular protective film before the corrosion products pile up. The characteristics of fast response time and quick self-healing rate meet the requirements of the magnesium alloy for self-healing in local regions.

Triple-stimuli-responsive nanocontainers assembled by water-soluble pillar[5]arene-based pseudorotaxanes for controlled release.

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.

Dual pH-Mediated Mechanized Hollow Zirconia Nanospheres.

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.

Mono-benzimidazole functionalized ß-cyclodextrins as supramolecular nanovalves for pH-triggered release of p-coumaric acid.

The self-complexation of mono-benzimidazole functionalized ß-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.

Mechanized silica nanoparticles based on reversible bistable [2]pseudorotaxanes as supramolecular nanovalves for multistage pH-controlled release.

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.

Graphene quantum dot-capped mesoporous silica nanoparticles through an acid-cleavable acetal bond for intracellular drug delivery and imaging.

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.