Acidic biofilm microenvironment-responsive ROS generation via a protein nanoassembly with hypoxia-relieving and GSH-depleting capabilities for efficient elimination of biofilm bacteria.

Reactive oxygen species (ROS) are widely considered to the effective therapeutics for fighting bacterial infections especially those associated with biofilm. However, biofilm microenvironments including hypoxia, limited H2O2, and high glutathione (GSH) level seriously limit the therapeutic efficacy of ROS-based strategies. Herein, we have developed an acidic biofilm microenvironment-responsive antibacterial nanoplatform consisting of copper-dopped bovine serum albumin (CBSA) loaded with copper peroxide (CuO2) synthesized in situ and indocyanine green (ICG). The three-in-one nanotherapeutics (CuO2/ICG@CBSA) are capable of releasing Cu2+ and H2O2 in a slightly acidic environment, where Cu2+ catalyzes the conversion of H2O2 into hydroxyl radical (•OH) and consumes the highly expressed GSH to disrupt the redox homeostasis. With the assistance of an 808 nm laser, the loaded ICG not only triggers the production of singlet oxygen (1O2) by a photodynamic process, but also provides photonic hyperpyrexia that further promotes the Fenton-like reaction for enhancing •OH production and induces thermal decomposition of CuO2 for the O2-self-supplying 1O2 generation. The CuO2/ICG@CBSA with laser irradiation demonstrates photothermal-augmented multi-mode synergistic bactericidal effect and is capable of inhibiting biofilm formation and eradicating the biofilm bacteria. Further in vivo experiments suggest that the CuO2/ICG@CBSA can effectively eliminate wound infections and accelerate wound healing. The proposed three-in-one nanotherapeutics with O2/H2O2-self-supplied ROS generating capability show great potential in treating biofilm-associated bacterial infections. STATEMENT OF SIGNIFICANCE: Here, we have developed an acidic biofilm microenvironment-responsive nanoplatform consisting of copper-dopped bovine serum albumin (CBSA) loaded with copper peroxide (CuO2) synthesized in situ and indocyanine green (ICG). The nanotherapeutics (CuO2/ICG@CBSA) are capable of releasing Cu2+ and H2O2 in an acidic environment, where Cu2+ catalyzes the conversion of H2O2 into •OH and consumes the overexpressed GSH to improve oxidative stress. With the aid of an 808 nm laser, ICG provides photonic hyperpyrexia for enhancing •OH production, and triggers O2-self-supplying 1O2 generation. CuO2/ICG@CBSA with laser irradiation displays photothermal-augmented multi-mode antibacterial and antibiofilm effect. Further in vivo experiments prove that CuO2/ICG@CBSA effectively eliminates wound infection and promotes wound healing. The proposed three-in-one nanotherapeutics show great potential in treating biofilm-associated bacterial infections.

Antibacterial and self-healing sepiolite-based hybrid hydrogel for hemostasis and wound healing.

The process of wound healing necessitates a specific environment, thus prompting extensive research into the utilization of hydrogels for this purpose. While numerous hydrogel structures have been investigated, the discovery of a self-healing hydrogel possessing favorable biocompatibility, exceptional mechanical properties, and effective hemostatic and antibacterial performance remains uncommon. In this work, a polyvinyl alcohol (PVA) hybrid hydrogel was meticulously designed through a simple reaction, wherein CuxO anchored sepiolite was incorporated into the hydrogel. The results indicate that introduction of sepiolite greatly improves the toughness, self-healing and adhesion properties of the PVA hydrogels. CuxO nanoparticles endow the hydrogels with excellent antibacterial performance towards Staphylococcus aureus and Escherichia coli. The application of hybrid hydrogels for fast hemostasis and wound healing are verified in vitro and in vivo with rat experiments. This work thereby demonstrates an effective strategy for designing biodegradable hemostatic and wound healing materials.

GSH-depleting and H2O2-self-supplying hybrid nanozymes for intensive catalytic antibacterial therapy by photothermal-augmented co-catalysis.

Nanozyme-based chemodynamic therapy (CDT) has shown tremendous potential in the treatment of bacterial infections. However, the CDT antibacterial efficacy is severely limited by the catalytic activity of nanozymes or the infection microenvironments such as insufficient hydrogen peroxide (H2O2) and overexpressed glutathione (GSH). Herein, a versatile hybrid nanozyme (MoS2/CuO2) is rationally constructed by simply decorating ultrasmall CuO2 nanodots onto lamellar MoS2 platelets of hydrangea-like MoS2 nanocarrier via a covalent Cu-S bond. The MoS2/CuO2 nanozyme exhibits the peroxidase-mimic activity for catalytically converting H2O2 produced by acid-triggered decomposition of the decorated CuO2 into hydroxyl radical (•OH). Meanwhile, the MoS2/CuO2 can consume GSH overexpressed in the infection sites via redox reaction mediated by polyvalent transition metal ions (Cu2+ and Mo6+) for enhanced CDT. More importantly, MoS2 support can promote the conversion of Cu2+ to Cu+ by a co-catalytic reaction based on the Mo4+/Mo6+ redox couples, and provide photonic hyperthermia (PTT) to augment the peroxidase-mimic activity. The developed MoS2/CuO2 nanozymes possesses a desirable catalytic property, as well as a remarkably improved antibacterial efficiency both in vitro and in vivo. Taken together, this study proposes a synergetic multiple enhancement strategy to successfully construct the versatile hybrid nanozymes for intensive in vivo PTT/CDT dual-mode anti-infective therapy. STATEMENT OF SIGNIFICANCE: Chemodynamic therapy (CDT) has shown great potentialities in the treatment of bacterial infections, while its therapeutic efficiency is severely limited by the infection microenvironments such as insufficient hydrogen peroxide (H2O2) and overexpressed glutathione (GSH). Here, we rationally construct a hybrid nanozyme (MoS2/CuO2) with peroxidase-like activity that can enhance CDT by regulating local microenvironments, that is, simultaneously self-supplying H2O2 and consuming GSH. Importantly, MoS2 support can promote the conversion of Cu2+ to Cu+ by the Mo4+/Mo6+ redox couples, and provide photonic hyperthermia (PTT) to augment the peroxidase-mimic activity. The developed MoS2/CuO2 shows desirable PTT/CDT dual-mode antibacterial efficacy both in vitro and in vivo. This study proposes a versatile hybrid nanozyme with multiple enhancement effects for intensive in vivo anti-infective therapy.

Ultra-thin silica shell-guarded nanoflares for high-fidelity live cell miRNA-21 imaging by fully avoiding the interference of biothiols.

We successfully constructed a new class of nanoflares based on ultra-thin silica-coated gold nanoparticles (Au@SiO2) with the covalent binding of nucleic acids, which demonstrated more resistance to biothiols than that exhibited in the traditional Au-S binding strategy, for imaging the target miRNA-21 with high fidelity in living cells.

Ultrastretchable, Self-Healable, and Tissue-Adhesive Hydrogel Dressings Involving Nanoscale Tannic Acid/Ferric Ion Complexes for Combating Bacterial Infection and Promoting Wound Healing.

Preventing bacterial infections and accelerating wound closure are essential in the process of wound healing. Current wound dressings lack enough mechanical properties, self-healing ability, and tissue adhesiveness, and the bacterial killing also relies on the use of antibiotic drugs. Herein, a well-designed hybrid hydrogel dressing is constructed by simple copolymerization of acrylamide (AM), 3-acrylamido phenylboronic acid (AAPBA), chitosan (CS), and the nanoscale tannic acid (TA)/ferric ion (Fe3+) complex (TFe). The resulting hydrogel possesses lots of free catechol, phenylboronic acid, amine, and hydroxyl groups and contains many reversible and dynamic bonds such as multiple hydrogen bonds and boronate ester bonds, thereby showing satisfactory mechanical properties, fast self-healing ability, and desirable tissue-adhesive performance. Benefiting from the high photothermal conversion efficiency of the TFe, the hydrogel exhibits satisfactory antibacterial activity against both Gram-positive and Gram-negative bacteria. Moreover, the embedded TFe also endows the hydrogel with good antioxidant activity, anti-inflammatory property, and cell proliferation to promote tissue regeneration. Remarkably, in vivo animal assays reveal that the hybrid hydrogel effectively eliminates biofilm bacteria in the wound sites and accelerates the healing process of infected wounds. Taken together, the developed versatile hydrogels overcome the shortcomings of traditional wound dressings and are expected to become potential antibacterial dressings for future biomedical applications.

A biofilm microenvironment-responsive one-for-all bactericidal nanoplatform for photothermal-augmented multimodal synergistic therapy of pathogenic bacterial biofilm infection.

Multimodal synergistic bactericidal agents display great potential for fighting biofilm infections. However, the rational design of biofilm microenvironment (BME)-activatable therapeutic agents with excellent specificities, effective eradications and minimal side effects remains a great challenge. Herein, we show a BME-responsive one-for-all bactericidal nanoplatform consisting of Fe3+-doped polydopamine (Fe/PDA)-capped ZnO nanoparticles with a successive assembly of methylene blue (MB) and poly(ethylene glycol) (PEG). In an acidic BME (pH 5.5), the constructed nanoagent (ZnPMp) can realize the co-delivery of dual metal ions (Zn2+ and Fe3+) and MB, and the latter shows an activated photodynamic antibacterial activity when irradiated with 635 nm laser. Zn2+ produced from acid-sensitive dissolution of ZnO is an effective chemical antibacterial agent. Additionally, the released Fe3+ is reduced to Fe2+ by glutathione (GSH) overexpressed in the BME to generate Fe2+/Fe3+ redox couples, which exhibit Fenton catalytic activity to convert endogenous H2O2 to hydroxyl radicals (˙OH) for chemodynamic sterilization and GSH depletion ability to improve ˙OH-induced oxidative damage. Interestingly, the hyperthermia caused by the Fe/PDA layer assisted with 808 nm laser can damage directly bacterial cells, accelerate the release of Zn2+, Fe3+and MB, and promote the catalytic activity of Fe2+/Fe3+ redox couples for photothermal-augmented multimodal antibiofilm therapy. With the help of dual lasers, ZnPMp displays the broad-spectrum antibacterial effect, inhibits effectively the formation of biofilms, and more importantly eliminates bacteria deep in mature biofilms. In addition, ZnPMp can be used to treat biofilm-related infections in vivo with excellent therapeutic performance and minimal toxicity. Overall, the developed ZnPMp may serve as a potential nano-antibacterial agent for intensive anti-infective therapy.

Rapid In Situ Deposition of Iron-Chelated Polydopamine Coating on the Polyacrylamide Hydrogel Dressings for Combined Photothermal and Chemodynamic Therapy of Skin Wound Infection.

Pathogenic bacterial infections of skin wounds have caused a significant threat to clinical treatment and human life safety. Here, we develop a bactericidal hydrogel dressing consisting of a polyacrylamide (PAM) hydrogel framework with in situ surface-deposition of iron-dopped polydopamine (FePDA). The prepared hydrogel dressing (FePDA-PAM) has a compact surface, good tensile strength, and excellent elastic recovery ability. The introduction of Fe3+ ions improve the photothermal therapy (PTT) efficiency of the PDA and endow the hydrogel dressing with chemodynamic therapy (CDT) properties. In vitro experiments show that the antibacterial effect of FePDA-PAM hydrogel on Staphylococcus aureus reach nearly 100% under the combined action of H2O2 and 808 nm near-infrared (NIR) laser, indicating an excellent combined antibacterial property of PTT and CDT. Furthermore, the FePDA-PAM + H2O2 + NIR treatment group in the in vivo antibacterial experiments displays lowest relative wound area and optimal wound healing within 5 days of treatment, thereby indicating the intensive skin wound disinfection. To summarize, the FePDA-PAM hydrogel has simple preparation and good biosafety. It may serve as a potential wound dressing for the combined PTT/CDT dual-mode antibacterial therapy.