Poly(l-glutamic Acid)-Based Microgels with Long-Term Synergistic Lubrication and MMP-Responsive Anti-Inflammatory Delivery for Osteoarthritis Therapy.

Osteoarthritis (OA) is a degenerative joint disease characterized by the failure of cartilage lubrication and persistent inflammation induced by friction-generated debris. Therefore, an effective OA treatment strategy should simultaneously enhance joint long-term lubrication and suppress inflammation. Toward this goal, we developed durable Lipo/PADM microgels via multiple cross-linking to integrate sustained lubrication with matrix metalloproteinase (MMP)-responsive dexamethasone release. The microgels maintained a low coefficient of friction of 0.029, remaining 24.3% lower than PBS after 8 weeks of in vitro degradation. In the MMP-rich OA microenvironment, ester-bond cleavage enabled sustained, on-demand drug release, reaching 70% within 14 days. Lipo/PADM microgels restored type II collagen expression, suppressed MMP-13 in bone marrow mesenchymal stem cells, and alleviated the OA-associated catabolic microenvironment. Intra-articular administration significantly reduced cartilage degeneration and delayed OA progression. These poly(glutamic acid)-based microgels offer a promising OA therapy through durable lubrication, responsive drug delivery, and prolonged intra-articular retention.