Nanomaterial-mediated autophagy regulation for osteoarthritis therapy: mechanisms and multifunctional applications

Osteoarthritis (OA) is a highly prevalent degenerative joint disease, characterized by progressive destruction of articular cartilage, synovial inflammation, and subchondral bone remodeling. Current clinical treatments primarily relieve symptoms yet rarely halt or reverse structural deterioration. Autophagy, a lysosome-dependent quality-control pathway, plays a context-dependent role in preserving chondrocyte viability and extracellular matrix homeostasis, and its dysfunction is increasingly recognized as a key contributor to OA progression. Leveraging tunable size, surface chemistry, and cargo programmability, nanomaterials enable targeted and sustained intra-articular delivery and can also act as intrinsically therapeutic or responsive components. Recent advances in nanomaterial-mediated autophagy modulation for OA are synthesized herein through the perspective of nanogeochemical interfaces at the synovial fluid-cartilage boundary, highlighting four complementary application modes: smart nanocarriers, intrinsically therapeutic nanomaterials, regenerative nanoscaffolds, and nanotheranostic platforms. Mechanistic pathways by which these systems influence OA pathology-including mTOR/AMPK signaling, oxidative stress and inflammatory cascades, chondrocyte apoptosis, extracellular matrix degradation, and joint immune microenvironment remodeling-are further delineated. Critical translational bottlenecks currently limiting clinical adoption are emphasized, encompassing biocompatibility and long-term intra-articular fate (retention versus clearance and degradation byproducts), standardization and reproducibility in material characterization and OA-relevant models, and the need for precise spatiotemporal control to avoid autophagy over- or under-activation. Ultimately, future directions are outlined, including biodegradable and stimulus-responsive designs, integrated imaging-guided personalization, and clinically aligned endpoints and manufacturing/regulatory strategies, all aimed at accelerating the development of safe and effective nano-enabled autophagy therapies for OA.