Dual-functional regulation of macrophage polarization by ROS-scavenging and chemokine-adsorbing heparin-based hydrogel microspheres for the treatment of chronic inflammatory diseases.

For chronic and progressive diseases such as osteoarthritis (OA) and diabetic wounds (DW), there are currently no effective drugs that can prevent or reverse their progression. Pathological overproduction of reactive oxygen species (ROS) and sustained inflammation are identified as key drivers of OA or DW progression. Herein, we developed a hydrogel microsphere system via cross-linking of star-shaped polyethylene glycol (star-PEG) with heparin, followed by surface functionalization with the radical scavenger Heparin @ PEG @ TEMPO (HPT) microspheres. The TEMPO-functionalized groups on the microspheres enable efficient scavenging of multiple ROS species, while the sulfated heparin-rich outer layer effectively captures pro-inflammatory chemokines and cytokines via electrostatic interactions. In vitro studies confirmed robust ROS scavenging and chemokine adsorption capacities; cellular assays further demonstrated that the microspheres promote macrophage polarization toward the anti-inflammatory M2 phenotype, thereby exerting potent anti-inflammatory effects. In a rat model of arthritis, treatment with these microspheres significantly preserved articular cartilage thickness, exhibited prolonged retention within the joint, and displayed excellent biocompatibility. Moreover, in a murine model of diabetic wound healing, treatment with these microspheres significantly accelerated wound closure and enhanced histological and structural indices of tissue repair, including re-epithelialization and collagen deposition. This work presents a promising dual-functional strategy for the localized therapy for chronic inflammatory diseases by integrating antioxidant and anti-inflammatory actions.