Novel Nanoplatform Based On Metal Nanoshell Structure For Treatment Of Drug-resistant Bacterial Infections To Promote Subcutaneous Wounds Healing

Due to the global overuse of antibiotics,the development of drug-resistant mutations in bacteria,and the increasing cost and difficulty of treatment,drug-resistant bacterial infections have become a serious threat to human health,and new antimicrobial therapies are urgently needed to help people get rid of this dilemma.New antimicrobial therapies include photothermal therapy(PTT),photodynamic therapy(PDT),metal ion sterilization therapy,gas therapy,immunotherapy,etc.,which are expected to be effective alternatives to antibiotics.Among the many photothermal agents,palladium nanoparticles,a precious metal,have received much attention from scholars because of their good efficacy and high biosafety,especially the development of palladium materials for near-infrared(NIR)light excitation has shown greater application prospects.However,the efficacy of a single photothermal therapy is often very limited,which requires the combination with other therapies such as photodynamic therapy to achieve 1+1>2 antimicrobial performance.The inflammation that accompanies drug-resistant bacterial infections is likewise a non-negligible problem.Inflammatory wounds with deep infections such as subcutaneous or muscular infections are particularly difficult to treat due to their hypoxic character,expressing high levels of inflammatory metabolites such as O2·and H2O2.Fortunately,precious metal nanomaterials such as palladium and gold possess the potential to modulate the inflammatory microenvironment by possessing catalytic activity for ROS degradation in addition to excellent photothermal properties,and therefore the construction of metal nanomaterials with both NIR photothermal properties and enzyme-like activity is of great significance in the treatment of infections with drug-resistant bacteria.To address the above realities,we developed UiO-66-NH2@Pdshell-IR780(UPI),a novel broad-spectrum bactericide.The system employs a metal organic framework(MOF)of UiO-66-NH2 as a template to grow rough Pd nanoshells UiO-66-NH2@Pdshell，and the plasmon resonance peak of Pd nanoshells is developed to the near-infrared-Ⅱ region(NIR-Ⅱ).The excellent photothermal conversion efficiency,preserved superoxide dismutase activity and photo-enhanced catalase activity of the prepared Pd nanoshells imply that the Pd nanoshells are well suited for in vivo photothermal therapy and modulation of the inflammatory microenvironment.At the in vivo therapeutic level,O2·-is converted to endogenous H2O2 by the SOD-like activity of UPI,and endogenous and exogenous H2O2 are continuously broken down to O2 by the CAT-like activity of UPI.The PTT efficacy of UPI is exerted under NIR-Ⅱ light,and the rate of O2 production is enhanced by light.PTT-PDT combination therapy is highly effective in clearing drug-resistant bacteria(MRSA)and its biofilm.The enzyme-like activity of UPI resulted in sustained degradation of ROS,increased O2 supply to alleviate the subcutaneous hypoxic microenvironment,and downregulation of HIF-1α.These factors triggered the transition from M1 macrophages to M2 macrophages,as evidenced by the downregulation of pro-inflammatory factors such as TNF-α and upregulation of anti-inflammatory factors such as IL-10,while further contributing to angiogenesis and collagen fiber production,and upregulation of CD31,which ultimately manifested in significantly faster wound healing.UPI,as a simple and reliable NIR-Ⅱlight-responsive reagent with good biocompatibility,it provides a novel idea for the design of a system to treat subcutaneous drug-resistant bacterial infections and promote wound healing.