An adhesion-switchable hydrogel dressing for painless dressing removal without secondary damage.

Hydrogels with strong adhesion to wet tissues are considered promising for wound dressings. However, the clinical application of adhesive hydrogel dressing remains a challenge due to the issues of secondary damage during dressing changes. Herein, we fabricated an adhesion-switchable hydrogel formed with poly(acrylamide)-co-poly(N-isopropyl acrylamide), quaternary ammonium chitosan and tannic acid. This hydrogel forms instant and robust adhesion to the skin at body temperature. However, as the temperature rises above the lower critical solution temperature (LCST), the hydrogel loses its adhesion towards the wound area due to the temperature-dependent volume phase transition of the copolymer, occurring around 45 °C. Consequently, the designed hydrogel can be easily detached from adhered tissues upon demand, providing a facile and effective method for painless dressing changes without secondary damage. This hydrogel holds great promise for long-term application in wound dressings.

Nanogalvanic Cells Release Highly Reactive Electrons in Tumors to Effectively Eliminate Tumors.

External stimuli triggering chemical reactions in cancer cells to generate highly reactive chemical species are very appealing for cancer therapy, in which external irradiation activating sensitizers to transfer energy or electrons to surrounding oxygen or other molecules is critical for generating cytotoxic reactive species. However, poor light penetration into tissue, low activity of sensitizers, and reliance on oxygen supply restrict the generation of cytotoxic chemical species in hypoxic tumors, which lowers the therapeutic efficacy. Here, this work presents galvanic cell nanomaterials that can directly release highly reactive electrons in tumors without external irradiation or photosensitizers. The released reactive electrons directly react with surrounding biomolecules such as proteins and DNA within tumors to destroy them or react with other surrounding (bio)molecules to yield cytotoxic chemical species to eliminate tumors independent of oxygen. Administering these nanogalvanic cells to mice results in almost complete remission of subcutaneous solid tumors and deep metastatic tumors. The results demonstrate that this strategy can further arouse an immune response even in a hypoxic environment. This method offers a promising approach to effectively eliminate tumors, similar to photodynamic therapy, but does not require oxygen or irradiation to activate photosensitizers.

Inflammation-induced subcutaneous neovascularization for the long-term survival of encapsulated islets without immunosuppression.

Cellular therapies for type-1 diabetes can leverage cell encapsulation to dispense with immunosuppression. However, encapsulated islet cells do not survive long, particularly when implanted in poorly vascularized subcutaneous sites. Here we show that the induction of neovascularization via temporary controlled inflammation through the implantation of a nylon catheter can be used to create a subcutaneous cavity that supports the transplantation and optimal function of a geometrically matching islet-encapsulation device consisting of a twisted nylon surgical thread coated with an islet-seeded alginate hydrogel. The neovascularized cavity led to the sustained reversal of diabetes, as we show in immunocompetent syngeneic, allogeneic and xenogeneic mouse models of diabetes, owing to increased oxygenation, physiological glucose responsiveness and islet survival, as indicated by a computational model of mass transport. The cavity also allowed for the in situ replacement of impaired devices, with prompt return to normoglycemia. Controlled inflammation-induced neovascularization is a scalable approach, as we show with a minipig model, and may facilitate the clinical translation of immunosuppression-free subcutaneous islet transplantation.

Co-delivery of a tumor microenvironment-responsive disulfiram prodrug and CuO2 nanoparticles for efficient cancer treatment.

Disulfiram (DSF) has been used as a hangover drug for more than seven decades and was found to have potential in cancer treatment, especially mediated by copper. However, the uncoordinated delivery of disulfiram with copper and the instability of disulfiram limit its further applications. Herein, we synthesize a DSF prodrug using a simple strategy that could be activated in a specific tumor microenvironment. Poly amino acids are used as a platform to bind the DSF prodrug through the B-N interaction and encapsulate CuO2 nanoparticles (NPs), obtaining a functional nanoplatform Cu@P-B. In the acidic tumor microenvironment, the loaded CuO2 NPs will produce Cu2+ and cause oxidative stress in cells. At the same time, the increased reactive oxygen species (ROS) will accelerate the release and activation of the DSF prodrug and further chelate the released Cu2+ to produce the noxious copper diethyldithiocarbamate complex, which causes cell apoptosis effectively. Cytotoxicity tests show that the DSF prodrug could effectively kill cancer cells with only a small amount of Cu2+ (0.18 µg mL-1), inhibiting the migration and invasion of tumor cells. In vitro and in vivo experiments have demonstrated that this functional nanoplatform could kill tumor cells effectively with limited toxic side effects, showing a new perspective in DSF prodrug design and cancer treatment.

DPA-Zinc around Polyplexes Acts Like PEG to Reduce Protein Binding While Targeting Cancer Cells.

Gene therapy holds great promise as an effective treatment for many diseases of genetic origin. Gene therapy works by employing cationic polymers, liposomes, and nanoparticles to condense DNA into polyplexes via electronic interactions. Then, a therapeutic gene is introduced into target cells, thereby restoring or changing cellular function. However, gene transfection efficiency remains low in vivo due to high protein binding, poor targeting ability, and substantial endosomal entrapment. Artificial sheaths containing PEG, anions, or zwitterions can be introduced onto the surface of gene carriers to prevent interaction with proteins; however, they reduce the cellular uptake efficacy, endosomal escape, targeting ability, thereby, lowering gene transfection. Here, it is reported that linking dipicolylamine-zinc (DPA-Zn) ions onto polyplex nanoparticles can produce a strong hydration water layer around the polyplex, mimicking the function of PEGylation to reduce protein binding while targeting cancer cells, augmenting cellular uptake and endosomal escape. The polyplexes with a strong hydration water layer on the surface can achieve a high gene transfection even in a 50% serum environment. This strategy provides a new solution for preventing protein adsorption while improving cellular uptake and endosomal escape.

Easy Access to Diverse Multiblock Copolymers with On-Demand Blocks via Thioester-Relayed In-Chain Cascade Copolymerization.

Multiblock copolymers are envisioned as promising materials with enhanced properties and functionality compared with their diblock/triblock counterparts. However, the current approaches can construct multiblock copolymers with a limited number of blocks but tedious procedures. Here, we report a thioester-relayed in-chain cascade copolymerization strategy for the easy preparation of multiblock copolymers with on-demand blocks, in which thioester groups with on-demand numbers are built in the polymer backbone by controlled/living polymerizations. These thioester groups further serve as the in-chain initiating centers to trigger the acyl group transfer ring-opening polymerization of episulfides independently and concurrently to extend the polymer backbone into multiblock structures. The compositions, number of blocks, and block degree of polymerization can be easily regulated. This strategy can offer easy access to a library of multiblock copolymers with ≈100 blocks in only 2 to 4 steps.

Biodegradable hydrogels with photodynamic antibacterial activity promote wound healing and mitigate scar formation.

Bacterial proliferation and the disordered extracellular matrix (ECM) at the wound site are the major reasons for delayed healing and abnormal scarring. The development of new multifunctional dressing materials that can effectively prevent scar formation without delaying wound healing remains a challenge. In this study, we construct a verteporfin-loaded biodegradable hydrogel (VP-gel) using hyaluronic acid and thiol-terminated 4-arm polyethylene glycol (PEG). The injectable VP-gel sustainably releases small doses of verteporfin in the wound microenvironment that generates reactive oxygen species (ROS) under red light irradiation to kill bacteria efficiently. Importantly, the sustained release of VP could also regulate TGF-ß family-induced cellular responses and the downstream signaling molecule Smad2 in fibroblasts to reduce myofibroblast differentiation, promoting ECM reconstruction and scarless wound healing. Immunohistochemical examination of wound healing and histomorphology in a mouse full-thickness wound model demonstrates excellent acceleration effects of VP-gel for infected wound healing. Therefore, VP-gel with anti-scarring and antibacterial activity, as well as enhanced infection wound healing ability shows great potential in the clinical treatment of scar healing for infected wounds.

Integrating Au and ZnO nanoparticles onto graphene nanosheet for enhanced sonodynamic therapy.

Sonodynamic therapy has attracted widespread attention for cancer treatment because of its noninvasiveness and high tissue-penetration ability. Generally, ultrasound irradiation of sonosensitizers produces separated electrons (e-) and holes (h+), which inhibits cancer by producing reactive oxygen species (ROS). However, the separated electrons (e-) and holes (h+) could easily recombine, lowering the yield of ROS and hindering the application of sonodynamic therapy (SDT). Herein, we present a highly efficient sonosensitizer system for enhanced sonodynamic therapy built on reduced graphene oxide (rGO) nanosheets, bridged ZnO and Au nanoparticles, coated with polyvinyl pyrrolidone (PVP). The ultrasound irradiation activates ZnO nanoparticles to generate separated electron-hole (e--h+) pairs, and the rGO nanosheets facilitate electron transfer from ZnO to Au nanoparticles because of the narrow band gap of rGO, which could efficiently restrain the recombination of the e--h+ pairs, thereby significantly augmenting the production of ROS to kill cancer cells, such as U373MG, HeLa, and CT26 cells. Moreover, rGO nanosheets integrated with Au nanoparticles could catalyze the endogenous decomposition of H2O2 into O2, which can alleviate hypoxic tumor microenvironment (TME). Therefore, the rational design of Au-rGO-ZnO@PVP nanomaterials can not only improve the efficiency of sonodynamic therapy, but also mitigate the hypoxic tumor microenvironment, which would provide a new perspective in the development of efficient sonosensitizers. Electronic Supplementary Material: Supplementary material (the UV-vis-NIR absorption spectra of the DPBF and the RhB, biological effect assessment of the Au-rGO-ZnO@PVP, and the inhibition rate of tumor under different treatments during the animal study) is available in the online version of this article at 10.1007/s12274-022-4599-5.

Tumor Microenvironment Triggered the In Situ Synthesis of an Excellent Sonosensitizer in Tumor for Sonodynamic Therapy.

An ultrasound-triggered sonodynamic therapy has shown great promise for cancer therapy. However, its clinical applications are very limited because the traditional sonosensitizers tend to suffer from very poor efficiency combined with low retention in cancer cells and low tumor selectivity. Therefore, sonosensitizers with higher effectivity, higher tumor cell retention, and higher tumor cell specificity are highly required. Herein, we constructed a Ti2C(OH)X nanosheet, which was a poor sonosensitizer but had a long circulation in the blood system. However, it was very interesting to find that the tumor microenvironment could in situ turn Ti2C(OH)X nanosheet into a novel and excellent sonosensitizer with a nanofiber structure in tumors, exhibiting excellent ability to generate reactive oxygen species (ROS) under ultrasound. Moreover, the nanofiber structure made it very difficult to get out of cancer cells, highly enhancing the retention of the sonosensitizer in the tumor, thereby enabling it to effectively and selectively kill cancer cells in vivo. Our findings demonstrate that the strategy of the tumor microenvironment triggering the in situ synthesis of an effective sonosensitizer in tumor provided a promising means to simultaneously increase the efficiency, sonosensitizer retention in cancer cells, and cancer selectivity, thereby effectively killing cancer cells but causing little damage to healthy tissues via the sonodynamic therapy.

Simultaneous nanocatalytic surface activation of pollutants and oxidants for highly efficient water decontamination.

Removal of organic micropollutants from water through advanced oxidation processes (AOPs) is hampered by the excessive input of energy and/or chemicals as well as the large amounts of residuals resulting from incomplete mineralization. Herein, we report a new water purification paradigm, the direct oxidative transfer process (DOTP), which enables complete, highly efficient decontamination at very low dosage of oxidants. DOTP differs fundamentally from AOPs and adsorption in its pollutant removal behavior and mechanisms. In DOTP, the nanocatalyst can interact with persulfate to activate the pollutants by lowering their reductive potential energy, which triggers a non-decomposing oxidative transfer of pollutants from the bulk solution to the nanocatalyst surface. By leveraging the activation, stabilization, and accumulation functions of the heterogeneous catalyst, the DOTP can occur spontaneously on the nanocatalyst surface to enable complete removal of pollutants. The process is found to occur for diverse pollutants, oxidants, and nanocatalysts, including various low-cost catalysts. Significantly, DOTP requires no external energy input, has low oxidant consumption, produces no residual byproducts, and performs robustly in real environmental matrices. These favorable features render DOTP an extremely promising nanotechnology platform for water purification.

Synthesis of Poly(thioester sulfonamide)s via the Ring-Opening Copolymerization of Cyclic Thioanhydride with N-Sulfonyl Aziridine Using Mild Phosphazene Base.

Providing access to diverse polymer structures is highly desirable, which helps to explore new polymer materials. Poly(thioester sulfonamide)s, combining both the advantages of thioesters and amides, however, are rarely available in polymer chemistry. Here, the ring-opening copolymerization (ROCOP) of cyclic thioanhydride with N-sulfonyl aziridine using mild phosphazene base, resulting in well-defined poly(thioester sulfonamide)s with highly alternative structures, high yields, and controlled molecular weights, is reported. Additionally, benefiting from the mild catalytic process, this ROCOP can be combined with ROCOP of N-sulfonyl aziridines with cyclic anhydrides to produce novel block copolymers.

Cyclic topology enhances the killing activity of polycations against planktonic and biofilm bacteria.

Bacterial biofilms, as a fortress to protect bacteria, enhance resistance to antibiotics because of their limited penetration, which has become a major threat to current anti-infective therapy. Antimicrobial polycations have received wide attention to kill planktonic bacteria because of their unique antimicrobial mechanism without drug resistance but it is still hard to kill the bacteria in the deep of the biofilm. Unlike linear polymers, the cyclic topology has been demonstrated with enhanced penetration in tissues, which is attributed to the lack of end groups, constrained conformation and a smaller hydrodynamic volume, opening a new sight of polycations in the antibacterial application against biofilms. Here, polycations with different topologies including linear and cyclic polycations were synthesized and their killing activity against planktonic and biofilm bacteria was studied. The experimental results showed the enhanced antibacterial activity of cyclic polycations for planktonic bacteria, which is presumably attributed to their smaller hydrodynamic volume, higher local density of positive charge and more interactions between cation units and the bacterial membrane than their linear analogues. Besides, cyclic polycations exhibit enhanced killing effect for biofilm bacteria and inhibition effect for biofilms with 5-7 times and 2-3 times enhancements than the linear polycations, respectively. Furthermore, an Escherichia coli infection model on mice was established and the therapeutic effects of cyclic and linear polycations were evaluated. Compared with the linear polycations, the cyclic polycations exhibited enhanced antibacterial activity with an ∼4 times increase, promoting the healing of the infected wounds. This work provides a new perspective in the development of antimicrobial polycations, which are promising therapeutic agents to kill planktonic and biofilm bacteria without drug resistance.

Phenylboronic acid-functionalized silver nanoparticles for highly efficient and selective bacterial killing.

With the widespread use of antibiotics, the number of severe infections caused by unknown pathogens is increasing and novel antibacterial agents with high antibacterial efficiency and selective bacterial killing are urgently needed. In this work, we developed a new kind of functional material based on silver nanoparticles (AgNPs), whose surfaces were functionalized with phenylboronic acid (AgNPs-PBAn). The phenylboronic acid groups on the surface of AgNPs-PBAn could form covalent bonds with the cis-diol groups of lipopolysaccharide or teichoic acid on the bacterial surface, which highly promoted the interaction between AgNPs-PBAn and bacteria, resulting in a very strong enhancement of their antibacterial action via membrane disruption. The scanning electron microscopy images revealed that the accumulation of phenylboronic acid-functionalized AgNPs on the bacterial surface is much more than that of the nonfunctionalized AgNPs. Importantly, the antibacterial efficiency of the phenylboronic acid-functionalized AgNPs on a series of bacteria is 32 times higher than that of bare AgNPs. Moreover, AgNPs-PBAn showed a high selectivity toward bacteria with an IC50 (half maximal inhibitory concentration to mammalian cells) more than 160 times its MBC (minimum bactericidal concentration). In a model of an E. coli-infected wound in vivo, AgNPs-PBAn could effectively kill the bacteria with an accelerated wound healing rate. This study demonstrates that phenylboronic acid surface functionalization is an efficient way to drastically promote the antibacterial activity of AgNPs, improving the selectivity of silver-based nanoparticles against a variety of bacteria.

Tug-of-War between Covalent Binding and Electrostatic Interaction Effectively Killing E. coli without Detectable Resistance.

Antimicrobial resistance in Gram-negative bacteria has become one of the leading causes of morbidity and mortality and a serious worldwide public health concern due to the fact that Gram-negative bacteria have an additional outer membrane protecting them from an unwanted compound invading. It is still very difficult for antimicrobials to reach intracellular targets and very challenging to treat Gram-negative bacteria with the current strategies. Here, we found that (o-(bromomethyl)phenyl)boronic acid was incorporated into poly((2-N,N-diethyl)aminoethyl acrylate) (PDEA), forming a copolymer (poly(o-Bn-DEA)) having both phenylboronic acid (B) and ((2-N,N-diethyl)amino) (DEA) units. Poly(o-Bn-DEA) exhibits very strong intramolecular B-N coordination, which could highly promote the covalent binding of phenylboronic acid with lipopolysaccharide (LPS) on the outer membrane of E. coli and lodge poly(o-Bn-DEA) on the LPS layer on the surface of E. coli. Meanwhile, the strong electrostatic interaction between poly(o-Bn-DEA) and the negatively charged lipid preferred tugging the poly(o-Bn-DEA) into the lipid bilayer of E. coli. The combating interactions between covalent binding and electrostatic interaction form a tug-of-war action, which could trigger the lysis of the outer membrane, thereby killing Gram-negative E. coli effectively without detectable resistance.

Single nanosheet can sustainably generate oxygen and inhibit respiration simultaneously in cancer cells.

In a tumor, the abnormal cancer cell proliferation results in an insufficient O2 supply, and meanwhile cancer cells consume O2 very fast. The imbalance between a low oxygen supply and overwhelming oxygen consumption results in a low oxygen concentration in solid tumors. Therefore, in order to relieve hypoxia in tumors, it is necessary to not only sustainably generate O2, but also inhibit mitochondrial respiration simultaneously. Here, we found that a single Ti2C(OH)2 nanomaterial not only can sustainably generate O2 but also simultaneously highly inhibits mitochondrial respiration via binding phosphorylation proteins onto the surface in cancer cells. Ce6 was linked onto Ti2C(OH)2, forming Ti2C(OH)2-Ce6. Ti2C(OH)2-Ce6 could highly relieve hypoxia in tumors via the combination of sustainable O2 generation and respiration inhibition, produce enough 1O2 to kill cancer cells via PDT, and also effectively convert the absorbed light energy into thermal energy to kill cancer cell via PTT, thereby highly enhancing the cancer therapy.

Correction: Single nanosheet can sustainably generate oxygen and inhibit respiration simultaneously in cancer cells.

Correction for 'Single nanosheet can sustainably generate oxygen and inhibit respiration simultaneously in cancer cells' by Wei-Qiang Huang et al., Mater. Horiz., 2021, DOI: .

Modulating Local Charge Distribution of Carbon Nitride for Promoting Exciton Dissociation and Charge-Induced Reactions.

The sustainable light can generate reduction and oxidation centers in situ through the generation of photoexcited electrons and holes in the presence of photocatalyst. However, the photoexcited electrons and holes have huge Coulombic attraction and high exciton binding energy due to the weak screening effect and dielectric properties in many low-dimensional conjugated polymers, such as carbon nitride. Reducing the exciton binding energy of carbon nitride and promoting the conversion of excitons into free charge carriers are necessary for improving the activity of photocatalytic reactions but still very challenging. Here, by introducing amino-cyano functional groups into carbon nitride, it is demonstrated that excitons can be effectively dissociated into electrons and holes by finely controlling the charge distribution of heptazine ring. It is found that carbon nitride with heptazine rings of positive charge distribution can greatly reduce the exciton binding energy to 24 from 71 meV. Compared with heptazine ring having negative charge distribution, heptazine ring with positive charge distribution can increase photocatalytic hydrogen production of carbon nitride by up to ten times. This work provides an easy way to promote the dissociation of excitons in carbon nitride by regulating the charge distribution.

Charge-reversal silver clusters for targeted bacterial killing.

Bacterial infections have become a common global health problem, causing a wide range of properties and life loss. The development of a highly efficient, low-toxicity and targeted bacterial agent is urgently needed. As a conventional antibacterial agent, silver nanoparticles have been used for a long time, but they are still unable to achieve targeted bacterial killing. Herein, we have prepared surface positively (Ag(+) nanoparticles) and negatively (Ag(-) nanoparticles) charged silver nanoparticles by reduction of AgNO3 to construct Ag(-)/Ag(+) clusters. The zeta potential of the Ag(-)/Ag(+) nanoclusters could be controlled by changing the ratio of Ag(-) nanoparticles to Ag(+) nanoparticles. The surface negatively changed silver nanoparticles were prepared from the reaction of methyl maleic anhydride with the amino on the surface positively changed silver nanoparticles. In the acidic environment, Ag(-) nanoparticles undergo charge reversal, and Ag(-)/Ag(+) clusters with negatively charged nanoparticles and big-size are transformed into positively charged nanoparticles with small size. The in vitro experimental results demonstrate that the positively charged nanoparticles can be well adsorbed on the negatively charged bacteria, exhibiting a high bactericidal ability. Furthermore, the in vivo skin wound healing experiment showed that the Ag(-)/Ag(+) clusters could serve as an efficient antibacterial agent to combat bacterial infection.

Facile Multicomponent Polymerization and Postpolymerization Modification via an Effective Meldrum's Acid-Based Three-Component Reaction.

Providing access to highly diverse polymer structures by multicomponent reactions is highly desirable; efficient Meldrum's acid-based multicomponent reactions, however, have been rarely highlighted in polymer chemistry. Here, the three-component reaction of Meldrum's acid, indole, and aldehyde is introduced into polymer synthesis. Direct multicomponent polymerization of Meldrum's acid, dialdehyde, and diindole can perform under mild conditions, resulting in complex Meldrum's acid-containing polymers with well-defined structures, and high molecular weights. Additionally, nearly quantitative postpolymerization modification can also perform via this Meldrum's acid-based multicomponent reaction. These results indicate that Meldrum's acid-based multicomponent reaction will be a potential tool to prepare novel polymers.

An NIR-activated polymeric nanoplatform with ROS- and temperature-sensitivity for combined photothermal therapy and chemotherapy of pancreatic cancer.

Nanomedicine has attracted growing attention due to its designability and functionality, as well as its excellent pharmacokinetics with limited side effects, and recently, combined therapies have become desirable as they can obtain enhanced therapeutic efficacy by using nanomedicine. Herein, we have reported a functional drug delivery system with a dual response to temperature and reactive oxygen species to efficiently eliminate pancreatic cancer cells in a combined therapy strategy. Functional micelles with camptothecin (CPT) in the core and indocyanine green (ICG) on the surface could effectively accumulate in tumor sites through the EPR effect. The ROS in the tumor microenvironment trigger the conversion of an amino-based copolymer to a carboxy based copolymer, releasing the loaded ICG to reduce the size of the micelles with high penetration in tumor tissue. On the one hand, under 808 nm light irradiation, the micelles will produce the heat to kill tumor cells via photothermal therapy. On the other hand, the generated heat could further trigger the transition of a copolymer from a hydrophobic to a hydrophilic state, releasing the loaded CPT into the deep tumor cells to achieve chemotherapy. The in vitro and in vivo experiments revealed that this combined therapy could combat pancreatic cancer cells with an enhanced therapeutic effect.