Diabetic foot ulcers, affecting millions worldwide, face impaired healing due to dysregulated macrophage polarization. However, the epigenetic mechanisms underlying aberrant macrophage polarization remain to be elucidated. This study introduces a multifunctional, exosome-based delivery platform that combines miR-493-5p–engineered M2 macrophage exosomes with piezoelectric GelMA microneedles to reprogram macrophage metabolism and epigenetics for diabetic wound healing. Engineered EXO@miR-493-5p are embedded in GelMA microneedles (MN) and delivered via a ZnO piezoelectric substrate with a nanosilver/GOx coating to provide antibacterial and antioxidant benefits. Ultrasound-induced electrostimulation enhances exosome deposition and endocytic uptake, enabling sustained, localized cargo release. Mechanistically, miR-493-5p targets HDAC1 to amplify histone H3K18 lactylation, activating the STAT6 axis and driving metabolic reprogramming toward M2 polarization with upregulation of Arg1. In vitro, EXO@miR-493-5p promote M2 markers and angiogenesis. In vivo, they accelerate wound closure, promote re-epithelialization, collagen deposition, and neovascularization, while reducing ROS and inflammation. The integrated platform offers a translatable, epigenetic-metabolic strategy for chronic diabetic wounds. Our work presents an Ag/GOx-loaded GelMA/ZnO microneedle system for engineered exosome (EXO@miR-493-5p) delivery. Upon ultrasonic induced piezoelectric effect, the system provides efficient delivery of exosomes in diabetic wounds. This orchestrates immunomodulation by reprogramming macrophages from a pro-inflammatory M1 to a reparative M2 phenotype, concurrently promoting angiogenesis, which synergistically enhances wound healing. • miR-493-5p promotes M2 macrophage polarization via lactate-induced histone lactylation. • miR-493-5p targets HDAC1 to enhance H3K18 lactylation and activate STAT6 for metabolic reprogramming. • Piezoelectric hydrogel microneedles integrate antibacterial, antioxidant, and electrostimulation for accelerated wound healing. • AgGOx@GelMAZnO MN@ EXO@miR system promotes diabetic wound closure through synergistic immunomodulation.
Chen et al. (2026) studied this question.