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Increasing occurrence of intrinsically antimicrobial-resistant, human pathogens and the protective biofilm-mode in which they grow, dictates a need for the alternative control of infectious biofilms. Biofilm bacteria utilize dispersal mechanisms to detach parts of a biofilm as part of the biofilm life-cycle during times of nutrient scarcity or overpopulation. We here identify recent advances and future challenges in the development of dispersants as a new infection-control strategy. Deoxyribonuclease (DNase) and other extracellular enzymes can disrupt the extracellular matrix of a biofilm to cause dispersal. Also, a variety of small molecules, reactive oxygen species, nitric oxide releasing compounds, peptides and molecules regulating signaling pathways in biofilms have been described as dispersants. On their own, dispersants do not inhibit bacterial growth or kill bacterial pathogens. Both natural, as well as artificial dispersants, are unstable and hydrophobic which necessitate their encapsulation in smart nanocarriers, like pH-responsive micelles, liposomes or hydrogels. Depending on their composition, nanoparticles can also possess intrinsic dispersant properties. Bacteria dispersed from an infectious biofilm end up in the blood circulation where they are cleared by host immune cells. However, this sudden increase in bacterial concentration can also cause sepsis. Simultaneous antibiotic loading of nanoparticles with dispersant properties or combined administration of dispersants and antibiotics can counter this threat. Importantly, biofilm remaining after dispersant administration appears more susceptible to existing antibiotics. Being part of the natural biofilm life-cycle, no signs of "dispersant-resistance" have been observed. Dispersants are therewith promising for the control of infectious biofilms. (C) 2021 Published by Elsevier Ltd on behalf of The editorial office of Journal of Materials Science & Technology.

Despite unprecedented successes of antibody-based cancer immunotherapy, the serious side effects and rapid clearance following systemic administration remain big challenges to realize its full potential. At the same time, combination immunotherapy using multiple antibodies has shown particularly promising in cancer treatment. It is noticed that the working mechanisms of natural holdase and foldase chaperone are desirable to overcome the limitations of therapeutic antibodies. Holdase chaperone stabilizes unfolded client and prevents it from activation and degradation, while foldase chaperone assists unfolded client to its native state to function. Here a holdase/foldase mimetic nanochaperone (H/F-nChap) to co-delivery two types of monoclonal antibodies (mAbs), αCD16 and αPDL1, and resiquimod (R848) is developed, which significantly improves cancer immunotherapy. The H/F-nChap presents holdase activity in blood and normal tissues that hides and protects mAbs from unnecessary targeted activation and degradation, thereby prolonging blood circulation and reducing immunotoxicity in vivo. Furthermore, H/F-nChap switches to foldase activity in the tumor microenvironment that exposes mAbs and releases R848 to enhance the engagement between NK cells and tumor cells and promote immune activation, respectively. The H/F-nChap represents a strategy for safe and spatiotemporal delivery of multiple mAbs, providing a promising platform for improved cancer immunotherapy.

A lipid named DCPA was synthesized under microwave‐assisted heating. DCPA possesses a pyridine betaine, hydrophilic group that can be complexed with water through hydrogen bonding (DCPA‐H2O). DCPA‐H2O liposomes became protonated relatively fast already at pH, A new lipid, DCPA, was prepared, possessing a hydrophilic, pyridine betaine group that can be hydrogen‐bonded with water yielding DCPA‐H2O. Self‐assembled DCPA‐H2O liposomes become rapidly protonated at relatively high pH (

The accumulation of soluble β-amyloid aggregates (sAβs) is one of the main culprits in Alzheimer’s disease (AD) progression, which can lead to synaptic dysfunction and subsequent neurodegeneration....

With the emergence of multidrug resistance (MDR) in many pathogens, bacterial infections are becoming a growing threat to public health. The frightening scenario is due largely to the formation of biofilms, in which the bacteria are extremely recalcitrant to the conventional antibiotic regimens. To address the emergence of MDR and biofilm-associated infections, numerous polymer-based materials have been designed and prepared recently. The subject of this perspective is the recent development of polymer-based materials that have been applied to combat multidrug-resistant pathogens, to prevent the formation of biofilms, or enhance the eradication efficacy to mature biofilms via killing biofilm-bacteria or dispersing biofilms. The advantages and shortcomings of these polymer-based materials are discussed, as well as the challenges we are facing in the clinical translation of these systems.

Bacterial biofilms, especially ones caused by multi-drug resistant strains, are increasingly posing a significant threat to human health. Inspired by nature, we report the fabrication of glucose oxidase-loaded iron-phenolic networks that can power the cascade reaction to generate free radicals to eradicate bacterial biofilms. A soft template, sodium deoxycholate, is employed to guarantee glucose oxidase activity during encapsulation, yielding the porous nanocomplexes after removing the template. The porous nature of nanocomplexes, characterized via transmission electron microscopy, N

Amyloid β peptide (Aβ) plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Currently, decreasing Aβ production and preventing Aβ aggregation are thought to be important strategies in anti-AD therapy. However, inhibiting Aβ production or aggregation in isolation is not sufficient to reverse the neurodegenerative process of AD patients in clinical testing. Here, a self-assembly molecular chaperone (SAMC) consisting of γ-secretase inhibitor DAPT and mixed-shell polymeric micelles is devised, serving as a bifunctional suppressor of AD. This two-in-one combinational system can simultaneously inhibit Aβ production and aggregation, which would contribute to enhancing the therapeutic effect by decreasing Aβ levels. Decorating a neuron-specific RVG29 peptide onto the surface, the DAPT-incorporated SAMC can specifically target neuronal cells and, thus, will relieve the strong side effect of DAPT on normal cells. Therefore, this combination strategy holds great potential to open up an avenue for AD treatment.

Protein therapeutics have been viewed as powerful candidates for cancer treatment by virtue of highly specific bioactivity and minimized adverse effects. However, the intracellular delivery of protein drugs remains enormously challenging due to multiple successive biological barriers

Photodynamic therapy has great potential for tumor ablation and the activation of antitumor immune responses. However, its overall therapeutic efficiency is often limited by the immunosuppressive tumor microenvironment. We developed a near-infrared light-excitable immunomodulating nano-photosensitizer (NeINP) that can improve reactive oxygen species production and regulate the immunosuppressive TME to improve photoimmunotherapy. The NeINP is composed of a photosensitive core and a pH-responsive polymer shell, which allows for NeINP loading and delivery of small-molecular immunomodulators to tumor sites for regulation of the immunosuppressive TME and effective photoimmunotherapy. Through the co-delivery of celecoxib and the NIR-triggered photodynamic core to tumors, the NeINP was shown to regulate the immunosuppressive TME and enhance antitumor immunity, leading to the elimination of residual tumor and reduction of metastasis and recurrence. The NeINP can be optimized to co-deliver other immunomodulators, and thus has potential as a universal platform for efficient, precise photoimmunotherapy.

Drug delivery systems (DDS) have extensively progressed over the past decades for eradicating the bacteria embedded in biofilms while minimizing the side effects of antimicrobials on the normal tissues. They possess potential in solving the challenges of intrinsic antimicrobial-resistance and poor penetration of antimicrobials into biofilms. However, the guidelines for developing a controlled DDS for combating bacterial biofilms are limited. In this review, classical mechanisms and mathematical models of DDS were summarized in order to lay the foundation of controlled DDS development. Strategies for building controlled DDS were proposed based on the process of biofilm formation, including surface coatings, fibers, nanoparticles as DDS to prevent biofilm formation and eradicate bacterial biofilm-associated infections. The challenges that still remain in DDS design were discussed and future directions were suggested. We hope this review could give a "road map" to inspire readers and boost the development of the new generation of controlled drug release system for antimicrobial applications.

Imparting ordered structures into otherwise amorphous hydrogels is expected to endow these popular materials with novel multiple-stimuli responsiveness that promises many applications. The current contribution reports a method to fabricate pure polymeric hydrogels with an inherent chiral internal structure by templating on the chiral nematic liquid crystal phase of a rodlike virus. A method was developed to form macroscopically homogeneous chiral templates by confinement induced self-assembly in the presence of monomers, cross-linkers and initiators. Polymerization induced gelation was performed without perturbing the elegant 3D chiral organization of the rodlike virus bearing double bonds. Furthermore, a suitable method was found to remove the organic virus template while keeping the desired polymeric replica intact, resulting in a pure polymeric hydrogel with a unique internal chiral feature that originates from the 3D chiral ordering of the cylindrical pores left by the virus. Multiple-stimuli responsiveness has been demonstrated and can be quantified by the change of the pitch of the chiral feature. The chiral structure endows the otherwise featureless hydrogel with a unique material property that might be used as a readout signal for sensing and acts as the basis for responsive, biomimetic nanostructured materials.

Precise control over self-assembly of peptides into adaptable nanostructures allows for emulating the dynamic organization of natural proteins and their sophisticated biological functions. Utilization of disease biomarkers as internal stimuli for manipulating the self-assembly of peptides bestows their adaptable features with a spatiotemporal resolution to satisfy the requirement of the performance of biomaterials. Reactive oxygen species (ROS) consisting of reactive ions or free radicals are overexpressed by pathological lesions and have been recognized as one of conventional biomarkers for disease progression. Despite the progress made over the past decade in stimulus-responsive self-assembly of peptides as well as the summarization of this progress, the specific reviews focusing on ROS-responsive self-assembly of peptides remain scarce. This review summarizes the progress achieved over the past decade of the ROS-responsive self-assembly of peptides into adaptable nanostructures and their applications in biomaterials. We focus on the chemical sources responsible for the ROS-sensitive behavior of peptides, in which the chemical moieties are incorporated into peptides as side chains, terminal groups, or backbone linkages. The ROS-responsive self-assembly of peptides into nanostructures with morphologies adaptable to ROS-oxidation and their applications in enzymatic catalysis, chemosensing, drug delivery, and tissue engineering will be highlighted. Understanding the established ROS-responsive peptide self-assembling systems allows us to provide perspectives for their further development and thereby elucidate their great potential in development of advanced biomaterials.

Immunosuppression is a key factor leading to a low therapeutic efficiency of the currently used immunotherapies. Monotherapies are unable to overcome immunosuppression because of the complex interplay of immune cells in tumors. Herein, we report a multifunctional nanomodulator (MFNM) as a carrier to deliver different types of immune modulators for comodulating multiple pathways. An MFNM has a core-shell structure, in which small-molecule drugs are encapsulated in a mesoporous silica nanoparticle (MSN) core with a pH-responsive polymer layer. Further, the polymeric shell provides active sites that are readily modifiable by multiple types of antibodies to regulate the immune-related processes. By codelivering cyclophosphamide (CTX), αPD-L1 (B7-H1), and α4-1BB (CD137L) monoclonal antibodies (mAbs) to tumors, an MFNM has been shown to regulate multiple immune pathways and enhance an antitumor immunity. As antibodies and small-molecule drugs loaded in an MFNM can be modified based on the tumor type, the MFNM provides a feasible platform for the development of advanced immunotherapies that require simultaneous modulation of multiple biological processes.

While poly(acyclic orthoester)s (PAOEs) have many appealing features for drug delivery, their application is significantly hindered by a lack of facile synthetic methods. Reported here is a simple method for synthesizing acyclic diketene acetal monomers from diols and vinyl ether, and their polymerization with a diol to first synthesize PAOEs. The PAOEs rapidly hydrolyze at lysosomal pH. With the help of a cationic lipid, ovalbumin, a model vaccine antigen was efficiently loaded into PAOEs nanoparticles using a double emulsion method. These nanoparticles efficiently delivered ovalbumin into the cytosol of dendritic cells and demonstrated enhanced antigen presentation over poly(lactic-co-glycolic acid) (PLGA) nanoparticles. PAOEs are promising vehicles for intracellular delivery of biopharmaceuticals and could increase the utility of poly(orthoesters) in biomedical research.

In the past decades, insulin delivery systems have been widely developed for diabetes treatment. Though a few works have investigated polymeric micelles with glucose and H2O2 dual-responsiveness fo...

In the past decades, insulin delivery systems have been widely developed for diabetes treatment. Though a few works have investigated polymeric micelles with glucose and H

Protein misassembly leads to the formation of dysfunctional and toxic molecular species relating to neurodegeneration in Parkinson's disease and Alzheimer's disease. Here, we tailored a nanochaperone (αS-nChap) for α-synuclein to regulate its assembly. The αS-nChap is capable of i) specifically recognizing α-synuclein; ii) dynamically capturing and stabilizing monomeric α-synuclein and retarding oligomerization; iii) tightly capturing oligomeric α-synuclein to prevent fibrillization; and iv) transporting α-synuclein oligomers to the lysosomal degradation system. The regulation of α-synuclein assembly by αS-nChap was studied in vitro. Moreover, the role of αS-nChap preventing α-synuclein pathology in cells and protecting neurons from apoptosis was investigated. The strategy of tailoring a nanochaperone to regulate aberrant assembly of pathogenic proteins provides important insights into protein misfolding diseases. We foresee that αS-nChap has therapeutic value for Parkinson's disease.

Polymeric nano-medicine has been widely studied in anti-cancer therapy and great achievements have been made over the past three decades. Though side effects of drugs such as toxicity are greatly reduced, the therapeutic efficacy has not been improved significantly so far, which maybe mainly because of the trade-off effects between oppositely required functions of nano-medicines at different steps in drug delivery, such as prolonged blood circulation vs. enhanced cellular uptake, and stable drug retention in transit vs. responsive release in cancer cells. To overcome the trade-off effect between blood circulation and cellular uptake, different functionalities, including surface charge reversal, shell-shedding, and surface self-assembly properties, have been designed for nano-carriers. The starting point of these strategies is endowing the nano-carriers with stealth character during blood circulation while transforming them into a more cell-interactive state to enhance cellular uptake. This review summaries the recent advances in designing powerful nano-carriers to overcome the trade-off effect between prolonging blood circulation and enhancing cellular uptake to improve the anti-cancer therapeutic efficacy.

Internalization ofStaphylococcus aureusby macrophages can inactivate bacterial killing mechanisms, allowing intracellular residence and dissemination of infection. Concurrently, these staphylococci can evade antibiotics that are frequently unable to pass mammalian cell membranes. A binary, amphiphilic conjugate composed of triclosan and ciprofloxacin is synthesized that self-assemble through micelle formation into antimicrobial nanoparticles (ANPs). These novel ANPs are stabilized through encapsulation in macrophage membranes, providing membrane-encapsulated, antimicrobial-conjugated NPs (Me-ANPs) with similar protein activity, Toll-like receptor expression and negative surface charge as their precursor murine macrophage/human monocyte cell lines. The combination of Toll-like receptors and negative surface charge allows uptake of Me-ANPs by infected macrophages/monocytes through positively charged, lysozyme-rich membrane scars created during staphylococcal engulfment. Me-ANPs are not engulfed by more negatively charged sterile cells possessing less lysozyme at their surface. The Me-ANPs kill staphylococci internalized in macrophages in vitro. Me-ANPs likewise kill staphylococci more effectively than ANPs without membrane-encapsulation or clinically used ciprofloxacin in a mouse peritoneal infection model. Similarly, organ infections in mice created by dissemination of infected macrophages through circulation in the blood are better eradicated by Me-ANPs than by ciprofloxacin. These unique antimicrobial properties of macrophage-monocyte Me-ANPs provide a promising direction for human clinical application to combat persistent infections.

Orally administrated probiotic bacteria can aid antibiotic treatment of intestinal infections, but their arrival at their intestinal target site is hampered by killing in the gastrointestinal tract and by antibiotics solely intended for pathogen killing. Carbon-quantum-dots are extremely small nanoparticles and can be derived from different sources, including bacteria. Here, we hypothesize that carbon-quantum-dots inherit antibacterial activity from probiotic source bacteria to fulfill a similar role as live probiotics in intestinal infection therapy. Physico-chemical analyses indicated that carbon-quantum-dots, hydrothermally derived from Bifidobacterium breve (B-C-dots), inherited proteins and polysaccharides from their source-bacteria. B-C-dots disrupted biofilm matrices of Escherichia coli and Salmonella typhimurium biofilms through extensive reactive-oxygen-species (ROS)-generation, causing a decrease in volumetric bacterial-density in biofilms. Decreased bacterial densities leave more open space in biofilms and have enhanced ciprofloxacin penetration and killing potential in an E. coli biofilm pre-exposed to probiotic B-C-dots. Pathogenic carbon-quantum-dots hydrothermally derived from E. coli (E-C-dots) did not disrupt pathogenic biofilms nor enhance E. coli killing potential by ciprofloxacin. B-C-dots were biosafe in mice upon daily administration, while E-C-dots demonstrated a decrease in white blood cell and platelet counts and an increase in C-reactive protein levels. Therefore, the way is paved for employing probiotic carbon-quantum-dots instead of viable, probiotic bacteria for synergistic use with existing antibiotics in treating intestinal infections.

Biological barriers significantly limit the delivery efficiency of drug delivery systems, resulting in undesired therapeutic effects. When designing a delivery system with optimized penetration behavior across the biological barriers, mechanical properties, such as deformability, are emerging as important parameters that need to be considered, although they are usually neglected in current research. Herein, a liquid core nanoparticle (LCN) composed of a polymer-encapsulated edible oil droplet is demonstrated. Owing to the unique structure in which the liquid oil core is encapsulated by a layer of highly hydrophilic and cross-linked polymer, the LCN exhibits high mechanical softness, making it deformable under external forces. With high deformability, LCNs can effectively penetrate through several important biological barriers including deep tumor tissue, blood-brain barriers, mucus layers, and bacterial biofilms. Moreover, the potential of the LCN as a drug delivery system is also demonstrated by the loading and release of several clinical drugs. With the capability of penetrating biological barriers and delivering drugs, LCN provides a potential platform for disease treatments, particularly for those suffering from inadequate drug penetration.

Design of endogenous stimuli-responsive amino acids allows for precisely modulating proteins or peptides under a biological microenvironment and thereby regulating their performance. Herein we report a noncanonical amino acid 2-nitroimidazol-1-yl alanine and explore its functions in creation of the nitroreductase (NTR)-responsive peptide-based supramolecular probes for efficient hypoxia imaging. On the basis of the reduction potential of the nitroimidazole unit, the amino acid was synthesized via the Mitsunobu reaction between 2-nitroimidazole and a serine derivate. We elucidated the relationship between the NTR-responsiveness of the amino acid and the structural feature of peptides involving a series of peptides. This eventually facilitates development of aromatic peptides undergoing NTR-responsive self-assembly by rationally optimizing the sequences. Due to the intrinsic role of 2-nitroimidazole in the fluorescence quench, we created a morphology-transformable supramolecular probe for imaging hypoxic tumor cells based on NTR reduction. We found that the resulting supramolecular probes penetrated into solid tumors, thus allowing for efficient fluorescence imaging of tumor cells in hypoxic regions. Our findings demonstrate development of a readily synthesized and versatile amino acid with exemplified properties in creating fluorescent peptide nanostructures responsive to a biological microenvironment, thus providing a powerful toolkit for synthetic biology and development of novel biomaterials.

Mitochondrion-targeting therapy exhibits great potential in cancer therapy but significantly suffers from limited therapeutic efficiency. Here we report on mitochondrion-targeting supramolecular antagonist-inducing tumor cell death via simultaneously promoting cellular apoptosis and preventing survival. The supramolecular antagonist was created via coassembly of a mitochondrion-targeting pentapeptide with its two derivatives functionalized with a BH3 domain or the drug camptothecin (CPT). While drug CPT released from the antagonist induced cellular apoptosis via decreasing the mitochondrial membrane potential, the BH3 domain prevented cellular survival through facilitating the association between the supramolecular antagonists and antiapoptotic proteins, thereby initiating mitochondrial permeabilization. Both in vitro and in vivo studies confirmed the combinatorial therapeutic effect arising from the BH3 domain and CPT drug within the supramolecular antagonist on cell death and thereby inhibiting tumor growth. Our findings demonstrate an efficient combinatorial mechanism for mitochondrial dysfunction, thus potentially serving as novel organelle-targeting medicines.

Adjusting the mechanical cues generated in cellular microenvironments is important for manipulating cell behaviour. Here we report on mechanically dynamic hydrogels undergoing directional domain sliding motion and investigate the effect of the well-defined mechanical motion on accelerating cell proliferation. The mechanically dynamic hydrogels were prepared via self-assembly of an amphiphilic peptide consisting of two alternating polar and nonpolar domains cross-linked by disulfide bonds at a nonsymmetrical position. The cross-linked peptide assembled into entangled nanofibers driven by the hydrophobic collapse involving a partial-length sequence due to the covalent constraint. Reduction of the disulfide bonds led to formation of non-equilibrated peptide bilayers, which underwent directional domain sliding motion along each promoted by the thermodynamically favourable transition from the partial to full hydrophobic collapse. The mechanical cues resulting from the directional domain sliding motion within the mechanically dynamic hydrogels accelerated cell proliferation when incubating cells on the hydrogel, compared to the thermodynamically static counterparts, via a mechanotransduction mechanism as supported by the facilitated translocation of yes-associated proteins into the nucleus of the cells. Our finding demonstrates the great potential of mechanically dynamic hydrogels as new-generation biomimetic extracellular matrices in tissue engineering and regeneration., Dynamic peptide hydrogels undergoing directional domain sliding movement upon release of covalent constraint accelerate cell proliferation through a mechanotransduction pathway.

A synergetic-equalisation coding scheme for pulse-amplitude modulation 4-level (PAM4) is proposed, based on which a 216 Gb/s 9-bit 8-wire 4-level (9B8W4L) transceiver is designed. According to the scheme, eight channels are grouped into four pairs based on the states for encoding. The two channels in pair transmit the same symbol in this unit interval (UI), and transmit different symbols in different pairs in the next UI. When decoding, the symbols in different channels are subtracted from and added with the others, following the grouping in the prior UI. From this, the first post-cursor inter-symbol interference is eliminated. Based on the proposed coding scheme, the PAM4 transceiver transmits 9-bit data by eight channels, giving a channel utilisation of 112.5%. The improvement of channel utilisation reduces the Nyquist frequency for the same data rate, which is of great significance for reducing channel loss and power consumption. The 216 Gb/s 9B8W4L transceiver with 1-tap feed-forward equaliser achieves a bit error rate

The formation of a protein corona on nanoprobes in the blood can not only reduce the delivery efficiency to their destination but also inhibit the functions of the nanoprobes. Herein, we report a multifunctional nanogel that can shield a single gold nanoparticle (AuNP) probe from interaction with the serum proteins, virtually eliminating protein corona formation on the nanoprobes. As a result, the delivery efficiency of the nanogel-encapsulated nanoprobes to tumors was dramatically enhanced. When the probes are delivered into target cells, the nanogel shells are degraded in acidic endosomes, where a proton sponge effect occurs instantaneously to release the AuNP probes into the cytoplasm to realize their bioimaging functions. We demonstrated the applicability of these probes for high-fidelity, noninvasive imaging of caspase activity in both cancer cells and in tumors. This strategy offers an exciting opportunity to design high-efficacy nanoprobes for in vivo imaging.

For type 1 and advanced type 2 diabetic patients, insulin replacement therapy with simulating on-demand prandial and basal insulin secretion is the best option for optimal glycemic control. However, there is no insulin delivery system yet could mimic both controlled basal insulin release and rapid prandial insulin release in response to real-time blood glucose changes. Here we reported an artificial insulin delivery system, mimicking physiological basal and prandial insulin secretion, to achieve real-time glycemic control and reduce risk of hypoglycemia. A phenylboronic acid (PBA)/galactosyl-based glucose-responsive insulin delivery system was prepared with insulin-loaded micelles embedded in hydrogel matrix. At the hyperglycemic state, both the hydrogel and micelles could swell and achieve rapid glucose-responsive release of insulin, mimicking prandial insulin secretion. When the glucose level returned to the normal state, only the micelles partially responded to glucose and still released insulin gradually. The hydrogel with increased crosslinking density could slow down the diffusion speed of insulin inside, resulting in controlled release of insulin and simulating physiological basal insulin secretion. This hydrogel-micelle composite insulin delivery system could quickly reduce the blood glucose level in a mouse model of type 1 diabetes, and maintain normal blood glucose level without hypoglycemia for about 24 h. This kind of glucose-responsive hydrogel-micelle composite may be a promising candidate for delivery of insulin in the treatment of diabetes.

Planar donor and acceptor (D-A) conjugated structures are generally believed to be the standard for architecting highly efficient photothermal theranostic agents, in order to restrict intramolecular motions in aggregates (nanoparticles). However, other channels of extra nonradiative decay may be blocked. Now this challenge is addressed by proposing an "abnormal" strategy based on molecular motion in aggregates. Molecular rotors and bulky alkyl chains are grafted to the central D-A core to lower intermolecular interaction. The enhanced molecular motion favors the formation of a dark twisted intramolecular charge transfer state, whose nonradiative decay enhances the photothermal properties. Result shows that small-molecule NIRb14 with long alkyl chains branched at the second carbon exhibits enhanced photothermal properties compared with NIRb6, with short branched chains, and much higher than NIR6, with short linear chains, and the commercial gold nanorods. Both in vitro and in vivo experiments demonstrate that NIRb14 nanoparticles can be used as nanoagents for photoacoustic imaging-guided photothermal therapy. Moreover, charge reversal poly(β-amino ester) makes NIRb14 specifically accumulate at tumor sites. This study thus provides an excited molecular motion approach toward efficient phototheranostic agents.

Novel artificial enzymes are highly desired to overcome the shortcomings of natural enzymes during industrial or biological applications. Here we designed and prepared nanogel-based artificial enzymes (NAEs) to mimic natural horseradish peroxidase (HRP) using a facile one-pot, scalable method. The poly(N-isopropylacrylamide) (PNIPAM) matrix provided a temperature-responsive and size-controllable scaffold for the NAEs, and 1-vinylimidazole (Vim) moieties stabilized the enzymatic centers (Hemin) through coordination interaction. The feeding ratios of the components to prepare NAEs were subsequently studied and optimized to ensure the NAEs possess the highest catalytic activity and stability. The optimized NAEs were quite stable and can maintain their catalytic activities over a broad range of heat or pH treatments, and a long storage period as well. The NAEs are active to catalytic oxidation of several azo compounds and their activities can easily be switched on/off by changing the surrounding temperature. Taken together, these easily made, highly stable, efficient and activity-switchable NAEs could mimic natural HRP while overcoming their shortcomings and have a potential in wastewater treatment and controllable catalysis.

Bacterial-infections are mostly due to bacteria in an adhering, biofilm-mode of growth and not due to planktonically growing, suspended-bacteria. Biofilm-bacteria are much more recalcitrant to conventional antimicrobials than planktonic-bacteria due to (1) emergence of new properties of biofilm-bacteria that cannot be predicted on the basis of planktonic properties, (2) low penetration and accumulation of antimicrobials in a biofilm, (3) disabling of antimicrobials due to acidic and anaerobic conditions prevailing in a biofilm, and (4) enzymatic modification or inactivation of antimicrobials by biofilm inhabitants. In recent years, new nanotechnology-based antimicrobials have been designed to kill planktonic, antibiotic-resistant bacteria, but additional requirements rather than the mere killing of suspended bacteria must be met to combat biofilm-infections. The requirements and merits of nanotechnology-based antimicrobials for the control of biofilm-infection form the focus of this Tutorial Review.

Nanoparticle-based combination therapy has been reported as one important treatment strategy to improve the therapeutic efficacy in cancer therapy. However, the traditional co-delivery method often suffers from serious coordination issues that fail to account for the differences in the action sites of each of the drugs, greatly counteracting the synergistic effects of combination agents. Herein, we report a pH-reduction dual responsive drug delivery system for the programmable release of combretastatin A-4 (CA4) and cis-platinum (CDDP). According to their spatial and temporal needs, such nanocarriers could firstly release CA4 in the perivascular sites by responding to the acidic microenvironment of the tumor, then further diffuse throughout the tumor and release CDDP upon redox when being taken-up by the cancer cells. With the help of such spatiotemporal release properties, CA4 and CDDP can target the endothelial cells of tumor vessels and the cancer cells in succession, giving rise to temporal and spatial synergisms. On one hand, the first released CA4 provided a complementary effect for improving tumor accumulation of nanocarriers and the delivery effect of CDDP. On the other hand, CA4 and CDDP respectively targeted their action sites, overall maximizing the therapeutic effect. More importantly, such spatiotemporal drug delivery ability is accomplished by the pH-reduction dual responsive design of the nanocarriers, and thus could also serve as a universal approach for programmable release of other combination agents to improve their synergistic effect in cancer therapy.

Diabetes is a chronic metabolic disorder disease characterized by high blood glucose levels and has become one of the most serious threats to human health. In recent decades, a number of insulin delivery systems, including bulk gels, nanogels, and polymeric micelles, have been developed for the treatment of diabetes. Herein, a kind of glucose and H2O2 dual-responsive polymeric nanogel was designed for enhanced glucose-responsive insulin delivery. The polymeric nanogels composed of poly(ethylene glycol) and poly(cyclic phenylboronic ester) (glucose and H2O2 dual-sensitive groups) were synthesized by a one-pot thiol-ene click chemistry approach. The nanogels displayed glucose-responsive release of insulin and the release rate could be promoted by the incorporation of glucose oxidase (GOx), which generated H2O2 at high glucose levels and H2O2 further oxidizes and hydrolyzes the phenylboronic ester group. The nanogels have characteristics of long blood circulation time, a fast response to glucose, and excellent biocompatibility. Moreover, subcutaneous delivery of insulin to diabetic mice with the insulin/GOx-loaded nanogels presented an effective hypoglycemic effect compared to that of injection of insulin or insulin-loaded nanogels. This kind of nanogel would be a promising candidate for the delivery of insulin in the future.

The poor tumor penetration of many nanomedicines severely limits their therapeutic efficiency. Although the combination of cell-penetrating peptides (CPPs) has been reported as a promising strategy to improve the penetration capability of nanoparticles, the nonspecific interactions of CPPs may reduce nanoparticles’ circulation time and increase their side effects, making them inapplicable in many in vivo settings. Herein, we report a ligand-switchable strategy to inhibit CPPs’ nonspecific interactions in the bloodstream and quickly reactivate their functions when entering into tumor sites. Due to the rapid phase transition of PAE, the CPPs can be completely hidden under the PEG corona in plasma, avoiding direct interaction with the immune cells and normal tissues. Once extravasation from blood vessels occurs, the acidic tumor microenvironment would trigger the exposure of the CPPs, promoting the diffusion of antitumor agents deep into the tumor sites. With this ligand-switchable property, nanocarriers are capable of achieving long durations of circulation, preferential accumulation and efficient tumor penetration simultaneously, giving rise to high antitumor activity and low adverse reactions, and also providing a universal approach to enable in vivo applications of CPPs as well as other nonspecific ligands.

Personalized cancer vaccination using nanomaterials holds great potential for cancer immunotherapy. Here, a nanochaperone (PBA-nChap) is tailored for in situ capture of tumor-associated antigens (TAAs) to improve cancer immunotherapy. The PBA-nChap is capable of i) efficiently capturing TAAs in situ; ii) protecting TAAs from degradation; iii) transporting TAAs to antigen-presenting cells and promoting cross-presentation. Intratumor injection of PBA-nChap in combination with pretreatment with photodynamic therapy (PDT) significantly enhances immune response and exhibits excellent antitumor efficacy. Moreover, nanovaccine prepared by simply co-culturing PBA-nChap with tumor cell fragments from surgery resected primary tumor in vitro synergized with immune checkpoint blockade (ICB) therapy can effectively inhibit tumor recurrence and metastasis after an operation. This work provides a promising platform for personalized cancer vaccination.

Fungal biofilms cause a major clinical problem with a shrinking armamentarium for treatment. Here, the design and synthesis of voriconazole-inbuilt zinc 2-methylimidazolates frameworks (V-ZIF) is reported. Voriconazole is built in through coordination-binding between zinc and voriconazole. These metal-organic-frameworks with inbuilt voriconazole, reduce inadvertent voriconazole-leakage, yield a zero-order release kinetics of voriconazole, aid antifungal penetration in Candida albicans biofilms, and prevent Candida aggregation yielding better dispersal. Once accumulated in an acidic C. albicans biofilm, voriconazole dissociates from the metal-organic framework to cause membrane-damage and killing of inhabiting fungi. Moreover, in a murine model, the V-ZIFs eradicate open-wound infections caused by C. albicans better than voriconazole in solution, with negligible side effects to the healthy tissues of major organs. Thus, V-ZIFs may provide a welcome addition to the antifungal armamentarium currently available for the treatment of fungal biofilms.

With the failure of various amyloid-β-targeted drugs for Alzheimer's disease (AD) in clinical trials, tau protein has gained growing attention as an alternative therapeutic target in recent years. The aggregation of tau exerts neurotoxicity, and its spreading in the brain is associated with increasing severity of clinical symptoms for AD patients; thus tau-targeting therapies hold great potential against AD. Here, a tau-targeted multifunctional nanoinhibitor based on self-assembled polymeric micelles decorated with tau-binding peptide is devised for AD treatment. Through the multivalent binding effect with the aggregating protein, this nanoinhibitor is capable of efficiently inhibiting tau protein aggregation, recognizing tau aggregates, and blocking their seeding in neural cells, thus remarkably mitigating tau-mediated cytotoxicity. Moreover, the formed nanoinhibitor-tau complex after binding is more easily degraded than mature tau aggregates, which will be conducive to enhance the therapeutic effect. We believe that this multifunctional nanoinhibitor will promote the development of new antitau strategies for AD treatment.

Antibodies have shown potential to deplete immunosuppressive factors in tumor tissues. However, intrinsic drawbacks, including time-consuming processes in preparation, high cost, and short half-life time, greatly restrict their applications. In this work, we report an antibody-like polymeric nanoparticle (APN) that is capable of specifically capturing and removing galectin-1 in tumor tissues, thereby enhancing the antitumor T-cell responses. The APN is composed of an albumin-polymer hybrid nanoparticle (core) and an acid-responsive PEG shell. The core of the APN contains multiple recognition units and Tuftsin peptides to capture target factors and activate macrophage-mediated phagocytosis, respectively. By employing galactose as recognition units, the APN facilitated the phagocytosis of galectin-1 in tumor tissues, thereby improving the antitumor responses of tumor-infiltrating T cells. Since the recognition units in the APN can be further replaced to capture and remove other peptides/proteins, the APN provides a feasible approach for the development of synthetic nanoformulations to regulate biological systems and treat diseases.

Four naphthopyran derivatives, namely, 3,3-bis(naphthalen-1-yl)-3H-naphtho[2,1-b]pyran, C33H22O, NP1, 3,3-bis([1,1′-biphenyl]-4-yl)-3H-naphtho[2,1-b]pyran, C37H26O, NP2, 3,3-bis(4-phenoxyphenyl)-3H-naphtho[2,1-b]pyran, C37H26O2, NP3, and 3,3-bis(4-methoxy-2-methylphenyl)-3H-naphtho[2,1-b]pyran, C29H26O3, NP4, were synthesized and their photochromic properties investigated. NP1–NP4 exhibited good photochromism in different solutions and in poly(methyl methacrylate) (PMMA) film under UV light irradiation. Solvatochromism and the electronic and steric effects of the substituent group on photochromism were analyzed and decolouration curves were found to fit a monoexponential kinetic decay in most cases. Single-crystal X-ray analysis of NP1 and NP2 revealed the structure–property relationships. Good fatigue resistance of NP1, both in solution and in the PMMA film, endows it with potential value for applications.

Nanochaperones have been designed and used for regulating the (re)folding of proteins, treating protein misfolding-related diseases, and, more recently, in drug delivery. Despite various successes, a complete understanding of the working mechanisms remains elusive, which represents a challenge for the realization of their full potential. Here, we thoroughly investigated the functioning of differently charged nanochaperones that regulate the refolding of thermally denatured lysozyme. We found that the balance between the capture and release of lysozyme clients that are controlled by nanochaperones plays a key role in regulating refolding. More importantly, the findings could be applied to other enzymes with various physicochemical properties. On the basis of these results, we could recover the activity of enzymes with high efficiency either after 20 days of storage at 40 °C or heating at high temperatures for 30-60 min. Our results provide important new design strategies for nanochaperone systems to improve their properties and expand their applications.

The inactivation of multimeric enzymes is a more complicated process compared with that of monomeric enzymes. Stabilization of multimeric enzymes is regarded as a challenge with practical values in enzyme technology. Temperature-sensitive copolymer chitosan