Hybrid macrophage-mitochondria extracellular vesicles for mitochondrial ROS regulation in diabetic wounds.

Abstract

Precise regulation of mitochondrial reactive oxygen species (mtROS) in macrophages is essential for reducing inflammation and promoting diabetic wound healing. However, achieving targeted and responsive mtROS modulation in specific cell remains challenging. Herein, we report a macrophage-mitochondria hybrid membrane derived artificial extracellular vesicle platform (C@AH-EV). C@AH-EV integrates biomimetic dual-targeting membranes with an mtROS activatable prodrug. It leverages membrane protein-mediated targeting of macrophage mitochondria to offer highly selective intracellular delivery. The payload is a ROS sensitive antioxidant prodrug, which incorporates lipid tails that enhance its drug loading efficiency in vesicles. Upon mtROS-triggered cleavage of the boronate ester bond, potent antioxidants were locally released within the mitochondria to restore redox balance. In vitro and in vivo studies demonstrate that C@AH-EVs effectively reprogram macrophages from an inflammatory toward an anti-inflammatory phenotype, thereby attenuating inflammation and accelerating diabetic wound repair. This work offers a promising direction for treating chronic inflammatory conditions.