Acid neutralization and metal-phenolic nanomedicine on-demand release microspheres for reversing cartilage degeneration.

Osteoarthritis (OA) is a degenerative joint disorder characterized by complex network dysregulation across the entire joint, which significantly compromises the efficacy of single-target therapeutic interventions. Pathological acidosis and magnesium ion (Mg2+) deficiency have been mechanistically associated with cartilage matrix degradation, abnormal subchondral bone remodeling, and chronic inflammation, collectively driving OA progression. In this study, we engineered porous PLGA microspheres (Cur-Mg/PLGA MPs) incorporating curcumin-modified magnesium hydroxide nanosheets to effectively neutralize excessive hydrogen ions and sustained the release of Mg-Cur nanocomplexes through microporous structures. This acid responsive and neutralization delivery system enhanced the therapeutic capacity of metal-phenolic nanomedicine in suppressing inflammatory responses, inhibiting osteoclast differentiation, and reducing chondrocyte catabolic activity, thereby achieving optimal cartilage preservation. Our in vitro experiments revealed that Cur-Mg/PLGA MPs exhibit remarkable chondroprotective effects under both inflammatory and acidic microenvironmental conditions. Moreover, in vivo evaluations demonstrated that this microsphere system can significantly alleviate OA-associated pain, effectively suppress osteoclast activation, and substantially maintain cartilage matrix homeostasis. Mechanistic investigations identified that Cur-Mg/PLGA MPs inhibit macrophage-to-osteoclast differentiation through ACOD1-mediated mitochondrial metabolic rewiring, ultimately disrupting the "acidosis-osteolysis "vicious cycle in OA pathogenesis. These findings present a novel comprehensive therapeutic strategy for OA management, which has demonstrated significant efficacy in rat models and hold promising potential for clinical translation.