Sustained release of metformin through an injectable hydrogel for synergistic macrophage reprogramming and ROS scavenging in the analgesic treatment of osteoarthritis

Osteoarthritis (OA), a prevalent joint disorder affecting millions worldwide, is primarily characterized by chronic pain driven by synovial M1-polarized macrophages, which perpetuate inflammation and generate excessive reactive oxygen species (ROS). However, existing pharmacological treatments offer limited long-term efficacy. Metformin, a known modulator of M1 macrophage polarization and ROS production, has demonstrated efficacy in alleviating OA pain via oral administration. Yet, its therapeutic translation is hindered by poor joint tissue bioavailability. Intra-articular (IA) delivery offers a clinically attractive solution, achieving high local drug concentrations while minimizing systemic exposure, but conventional IA formulations are rapidly cleared from the joint space, restricting their efficacy. We designed an injectable hydrogel based on dopamine (DA) and carboxyl-terminated Pluronic F127 (F127) and crosslinked the hydrogel network via oxidative coupling between catechol groups using an H2O2/horseradish peroxidase (HRP) system (termed ‘F127-DA-HRP’) to deliver metformin (termed ‘Met-F127-DA-HRP’) intra-articularly in a sustained manner. The Met-F127-DA-HRP hydrogel scavenges ROS through its catechol groups and sustained metformin release, while also promoting M1-to-M2 macrophage repolarization and suppressing inflammatory cytokines. Importantly, a single IA injection of Met-F127-DA-HRP hydrogel maintained 2-fold higher metformin concentrations in joint tissues compared to Met-F127 hydrogel, with sustained retention for up to 30 days. In monosodium iodoacetate (MIA)-induced OA, IA injection of Met-F127-DA-HRP hydrogel successfully relieved OA pain and ameliorated synovitis with long-lasting effects. Collectively, this work introduces a potent therapeutic strategy for the sustained management of OA pain by utilizing an injectable hydrogel to prolong the IA residency of metformin, offering long-acting IA analgesia through macrophage-directed immunomodulation.