# MicroRNA-493-5p engineered exosomes delivered via piezoelectric microneedles for epigenetic modulation of macrophages in diabetic wound healing

## TL;DR

A new system uses engineered exosomes and piezoelectric microneedles to improve healing in diabetic wounds by reprogramming immune cells.

## Contribution

A novel exosome delivery platform using miR-493-5p and piezoelectric microneedles for epigenetic modulation of macrophages in diabetic wound healing.

## Key findings

- MiR-493-5p promotes M2 macrophage polarization via lactate-induced histone lactylation.
- The AgGOx@GelMAZnO MN@EXO@miR system accelerates diabetic wound closure through synergistic immunomodulation.
- The system reduces ROS and inflammation while promoting re-epithelialization and neovascularization in vivo.

## Abstract

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.Image 1

•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.

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.