Targeting Starvation Therapy for Diabetic Bacterial Infections with Endogenous Enzyme-Triggered Hyaluronan-Modified Nanozymes in the Infection Microenvironment

The high-glycemic microenvironment of diabetic wounds promotes bacterial proliferation, leading to persistent infections and delayed wound healing. This poses a significant threat to human health, necessitating the development of new nanodrug visualization platforms. In this study, we designed and synthesized cascade nano-systems modified with targeted peptide and hyaluronic acid for diabetic infection therapy. The nano-systems were able to target the site of infection using LL-37, and in the microenvironment of wound infection, the hyaluronic acid shell of the nano-systems was degraded by endogenous hyaluronidase. This precise degradation released a cascade of nano-enzymes on the surface of the bacteria, effectively destroying their cytoskeleton. Additionally, the metals in the nano-enzymes provided a photo-thermal effect, accelerating wound healing. The cascade nano-visualization platform demonstrated excellent bactericidal efficacy in both in vitro antimicrobial assays and in vivo diabetic infection models. In conclusion, this nano-system employs multiple approaches including targeting, enzyme-catalyzed therapy, photothermal therapy, and chemodynamic therapy to kill bacteria and promote healing. The Ag@Pt-Au-LYZ/HA-LL-37 formulation shows great potential for the treatment of diabetic wounds.