Abstract

Osteoarthritis (OA) is a common degenerative joint disease with limited disease-modifying therapies. Emerging evidence suggests that epigenetic dysregulation contributes to cartilage degeneration, but effective strategies to selectively target these pathways remain lacking. Here we show that the BRD4/Nav1.7 axis drives inflammatory and metabolic dysfunction in OA. Integrated single-cell and transcriptomic analyses identify BRD4 as a key regulator that enhances Nav1.7 transcription, promoting mitochondrial impairment and catabolic activation in chondrocytes. To therapeutically target this pathway, we develop a biomimetic hydrogel system incorporating chondrocyte membrane-coated nanoparticles for cartilage-specific delivery of a BRD4 proteolysis-targeting chimera (PROTAC), a molecule designed to induce selective protein degradation. This nanoplatform enables efficient intra-articular delivery, immune evasion and targeted retention in cartilage. Treatment suppresses inflammatory responses, restores mitochondrial function and reduces cartilage degeneration and pain behaviors in two mouse models of OA. These findings establish targeted BRD4 degradation as a disease-modifying strategy and provide a precision nanotherapeutic platform for OA. Osteoarthritis is driven by epigenetic dysregulation, yet targeted therapies remain elusive. Here, the authors develop a cartilage-targeting hydrogel delivering BRD4-degrading PROTACs to suppress the BRD4- Nav1.7 axis and alleviate osteoarthritis.