A multi-enzyme cascade microneedle reaction system for hierarchically MRSA biofilm elimination and diabetic wound healing

Abstract

The existence of biofilm remains a significant impediment to the healing of chronic wounds, including diabetic wounds. The dense extracellular polymeric substance (EPS) barrier of biofilms leads to poor drug permeability, making biofilms eradication a challenging task. Additionally, high glucose levels hinder the process of wound healing. To address these issues, we developed a multi-enzyme cascade microneedle system (MN) by combining enzymatic biofilm disruption with GOx-based chemodynamic therapy (CDT) for the first time. The microneedle tip dissolves quickly and delivers α-amylase and glucose oxidase-loaded metal–organic framework MIL-101 (M@G) into the biofilm’s interior. The α-amylase disintegrates the EPS structure, making the bacteria vulnerable and producing glucose as a substrate for the next cascade reaction. Next, GOx uses the glucose produced from EPS degradation and present at the wound site to produce significant amounts of H2O2, which is then transformed to reactive oxygen species (ROS) through MIL-101. The system eradicates methicillin-resistant Staphylococcus aureus (MRSA) biofilms by sequentially destroying EPS, consuming glucose at the wound, and self-supplying H2O2 to produce ROS, thereby reducing glucose concentrations and concurrently decreasing bacterial infection and inflammatory responses. Additionally, the pro-angiogenic peptide functionalized hydrogel (Gel-Q-M) serves as a backing to promote collagen deposition and angiogenesis, thereby accelerating the healing of chronic wound. In conclusion, the constructed MN platform showed excellent anti-biofilm and angiogenic properties in vitro, which could effectively eliminate biofilm, reduce inflammation and promote diabetic wound repair.