ROS-Triggered Microgels for Programmable Drug Release in Volumetric Muscle Loss Repair

Volumetric muscle loss (VML), frequently resulting from traumatic or surgical damage, causes significant muscle mass depletion and fibrosis, and presents major challenges to effective regeneration. In this study, reduced graphene-containing hyaluronic acid microgels (rGHMs) are developed as a multifunctional platform for reactive oxygen species (ROS)-scavenging and ROS-responsive drug delivery to treat VML. The rGHMs are synthesized via a water-in-oil emulsion and subsequent chemical reduction. rGHMs demonstrate superior antioxidative capability, curcumin loading efficiency, and ROS-mediated drug release properties compared to HA microgels (HMs) and unreduced graphene-oxide containing HA microgels (GHMs). In particular, curcumin-loaded rGHMs (Cur/rGHMs) significantly facilitate curcumin release with a 2.6-fold increase under 1 mm H₂O₂ compared to non-ROS conditions, demonstrating programmable, ROS-triggered release kinetics. In vitro studies confirm that rGHMs are cytocompatible and protect C2C12 myoblasts from ROS-induced damage. In vivo studies using a mouse VML model reveal that Cur/rGHMs significantly enhance skeletal muscle regeneration, as evidenced by an increased number of centronucleated muscle cells, 89.0 % muscle strength recovery, 51.0 % reduction in fibrosis, a 2.3-fold increase in vascularization, and attenuated inflammatory macrophage infiltration. These ROS-responsive microgels enable programmed curcumin delivery in oxidative environments, offering a promising therapeutic strategy for skeletal muscle regeneration in VML.