A Zn-MOF-GOx-based cascade nanoreactor promotes diabetic infected wound healing by NO release and microenvironment regulation.

Diabetic wound healing is a great clinical challenge due to the microenvironment of hyperglycemia and high pH value, bacterial infection and persistent inflammation. Here, we develop a cascade nanoreactor hydrogel (Arg@Zn-MOF-GOx Gel, AZG-Gel) with arginine (Arg) loaded Zinc metal organic framework (Zn-MOF) and glucose oxidase (GOx) based on chondroitin sulfate (CS) and Pluronic (F127) to accelerate diabetic infected wound healing. GOx in AZG-Gel was triggered by hyperglycemic environment to reduce local glucose and pH, and simultaneously produced hydrogen peroxide (H2O2) to enable Arg-to release nitric oxide (NO) for inflammation regulation, providing a suitable microenvironment for wound healing. Zinc ions (Zn2+) released from acid-responsive Zn-MOF significantly inhibited the proliferation and biofilm formation of S.aureus and E.coli. AZG-Gel significantly accelerated diabetic infected wound healing by down-regulating pro-inflammatory tumor necrosis factor (TNF)-α and interleukin (IL)-6, up-regulating anti-inflammatory factor IL-4, promoting angiogenesis and collagen deposition in vivo. Collectively, our nanoreactor cascade strategy combining "endogenous improvement (reducing glucose and pH)" with "exogenous resistance (anti-bacterial and anti-inflammatory)" provides a new idea for promoting diabetic infected wound healing by addressing both symptoms and root causes. STATEMENT OF SIGNIFICANCE: A cascade nanoreactor (AZG-Gel) is constructed to solve three key problems in diabetic wound healing, namely, hyperglycemia and high pH microenvironment, bacterial infection and persistent inflammation. Local glucose and pH levels are reduced by GOx to provide a suitable microenvironment for wound healing. The release of Zn2+ significantly inhibits bacterial proliferation and biofilm formation, and NO reduces wound inflammation and promotes angiogenesis. The pH change when AZG-Gel is applied to wounds is expected to enable the visualization of wound healing to guide the treatment of diabetic wound. Our strategy of "endogenous improvement (reducing glucose and pH)" combined with "exogenous resistance (anti-bacterial and anti-inflammatory)" provides a new way for promoting diabetic wound healing.

Photodynamic Alginate Zn-MOF Thermosensitive Hydrogel for Accelerated Healing of Infected Wounds.

Antibiotic resistance reduces the effectiveness of infected wound healing, and it is necessary to develop a new strategy to promote infected wound healing without using antibiotics. Here, we develop a Chlorin e6 (Ce6)-loaded zinc-metal-organic framework (MOF) thermosensitive hydrogel (Ce6@MOF-Gel) based on alginate and poly(propylene glycol) 407, which enhances antibacterial effects and promotes infected wound healing by a novel strategy of combining zinc-MOF with photodynamic therapy (PDT). Zinc-MOF can realize acid-responsive release of Ce6 and improve antibacterial performance without drug resistance by destroying the integrity of bacterial cell membranes and enhancing the production of bacterial reactive oxygen species (ROS). Additionally, Ce6@MOF-Gel enhances the stability, solubility, and photodynamic properties of Ce6. More importantly, Ce6@MOF-Gel reduces inflammation and promotes collagen deposition and re-epithelialization to facilitate infected wound healing. Collectively, the photodynamic MOF-based hydrogel provides a new, efficient, and safe way for accelerated healing of infected wounds.

Hyaluronic Acid-Based CuS Nanoenzyme Biodegradable Microneedles for Treating Deep Cutaneous Fungal Infection without Drug Resistance.

Deep cutaneous fungal infection (DCFI) is difficult to be treated by the traditional topical application due to low drug transdermal efficiency, poor fungicidal effect, and easy to develop drug resistance. Here, we report a novel biodegradable microneedle patch (CuS/PAF-26 MN) for DCFI treatment. CuS/PAF-26 MN is composed of hyaluronic acid (HA) and sodium carboxymethylcellulose (CMC-Na), which can simultaneously deliver copper sulfide nanoenzyme (CuS NE) and antimicrobial peptide (PAF-26). CuS NE catalyzes hydrogen peroxide to produce reactive oxygen species (ROS), and PAF-26 directly destroys the cell membrane of fungi. The combination of ROS toxicity produced by CuS NE and the destruction of fungal membrane by PAF-26 shows strong antifungal activities without drug resistance. The antifungal effect of CuS/PAF-26 MN is significantly superior to that of traditional ointment, CuS MN or PAF-26 MN in a DCFI mouse model. Therefore, CuS/PAF-26 MN shows a promising application prospect for treating DCFI.