Bridging the gap in OA therapeutics: Bioengineered strategies to target osteoclast–chondrocyte crosstalk

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, subchondral bone remodeling, and joint microenvironment imbalance. Emerging evidence identifies pathological osteoclast-chondrocyte crosstalk as a key OA driver, mediated through RANKL/RANK/OPG, NF-κB, HIF-2α, and VEGF signaling pathways that create a destructive bone-cartilage feedback loop. This review examines: (1) molecular mechanisms underlying this cellular communication, (2) therapeutic small-molecule inhibitors targeting CatK, MMP-13, NFATc1, and Runx2, and (3) innovative nanomedicine approaches including tissue-specific nanoparticles, smart delivery systems, and combination therapies. We evaluate these strategies' preclinical validation in animal and organoid models while addressing translational challenges in biosafety, tissue targeting, and personalized delivery. By integrating intercellular signaling knowledge with advanced therapeutic technologies, we provide a framework for developing disease-modifying OA treatments that bridges basic research with clinical precision medicine applications.