MicroRNA-493-5p Engineered Exosomes Delivered via Piezoelectric Microneedles for Epigenetic Modulation of Macrophages in Diabetic Wound Healing

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.