Micro–nano integrated platforms for osteoarthritis therapy: From spatial manipulation to cellular reprogramming

Clinical intervention for osteoarthritis (OA) has long been hampered by complex intra-articular physiological barriers, including rapid synovial clearance, the dense penetration resistance of the cartilage extracellular matrix (ECM), and a progressively deteriorating pro-inflammatory microenvironment. Conventional single-scale delivery systems frequently struggle to balance sustained retention with deep tissue penetration. Recently, micro-nano composite structures-engineered through the sophisticated integration of microscale matrices and nanoscale functional units-have catalyzed a paradigm shift from passive "space-filling" to active "fate modulation." This review systematically delineates the recent advancements in micro-nano platforms for OA therapy. We first evaluate how advanced fabrication strategies, such as microfluidics, 3D bioprinting, and hierarchical emulsification, govern the spatiotemporal arrangement of these structures. Subsequently, we explore the mechanisms by which these trans-scale systems achieve prolonged joint residence, deep ECM infiltration, and precise immunomodulation of macrophages and stem cells. Furthermore, the roles of micro-nano architectures in recapitulating the biomimetic properties (topological, mechanical, and biochemical) of native cartilage and stimulating endogenous repair are highlighted. Finally, we provide a critical appraisal of the challenges hindering clinical translation, including scalability, biosafety margins, and the future of intelligent closed-loop designs. The development of micro-nano composite systems not only offers high-efficiency "cell-free therapy" for OA but also establishes a novel scientific paradigm for precision regenerative medicine in degenerative diseases.