A COX-2 PROTAC Nanodrug for osteoarthritis therapy via enhancing cartilage repair and reprogramming macrophage polarization.

Osteoarthritis (OA) is a chronic joint disorder characterized by synovitis and articular cartilage degeneration, representing a major unmet clinical challenge that demands innovative therapeutic strategies. Inhibition of cyclooxygenase-2 (COX-2) represents a promising approach for OA management, but its application is limited by drug-related side effects. In this study, we developed a pomalidomide-based proteolysis-targeting chimera (PROTAC) nanodrug (PMKTP@NP) through self-assembly of a COX-2-targeting polymer, which simultaneously mitigates cartilage damage and modulates macrophage polarization for OA therapy. PMKTP@NP was synthesized by integrating a COX-2 inhibitor, pomalidomide (a cereblon E3 ligase recruiter), and biocompatible PEG. In vitro studies demonstrated that PMKTP@NP effectively degraded intracellular COX-2 via the ubiquitin-proteasome system, achieving near-complete COX-2 clearance at 48 h. Concurrently, PMKTP@NP repolarized pro-inflammatory M1 macrophages toward the anti-inflammatory M2 phenotype, thereby enhancing chondrocyte proliferation and suppressing apoptosis. Intravenous injection of PMKTP@NP in a surgically induced destabilization of the medial meniscus (DMM) mouse model significantly mitigated OA progression as evidenced by restored cartilage thickness, reduced Osteoarthritis Research Society International scores, and synovial M2 macrophage enrichment. These findings underscore PMKTP@NP as a dual-functional nanotherapeutic strategy for targeted protein degradation and immunomodulation, offering a transformative paradigm for OA therapy and potentially other inflammatory joint pathologies.