Osteoarthritis (OA) is a degenerative joint disease and the leading cause of joint-related disability worldwide. In current clinical treatment approaches, drug therapy remains widely used, primarily through systemic administration of anti-inflammatory drugs and intra-articular injections. However, effective OA treatment remains challenging due to several barriers: the continuous flow of synovial fluid, the dense and negatively charged cartilage matrix, and the resulting poor drug accumulation at target sites. Moreover, rapid drug clearance from the synovial cavity, frequent dosing requirements, and increased risk of adverse effects further limit treatment efficacy. Recent advancements in intra-articular drug delivery systems, constructed from biological, organic, and inorganic materials, have demonstrated significant potential for OA treatment. Leveraging nanotechnology, these systems not only enhance targeted drug delivery to specific lesions but also enable controlled drug release at inflammatory sites through the optimization of nanocarrier design. This review explores the most innovative strategies for intra-articular drug delivery systems and the key challenges associated with this field. We discuss the development and research progress of emerging delivery technologies, including nanoparticles, liposomes, hydrogels, microspheres, and exosomes. Finally, we highlight the current limitations of intra-articular drug delivery systems and their prospects, aiming to provide valuable insights for further research and clinical translation. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) involves the progressive degradation of articular cartilage components, such as type II collagen and aggrecan, leading to chronic disability. Traditional treatments (systemic drugs, surgery) face limitations like poor targeting, short half-life, and invasiveness. While intra-articular injections enable localized delivery, rapid clearance, cartilage matrix barriers, and inadequate tissue penetration hinder efficacy. Recent advances in nanomaterials and drug delivery systems offer solutions. Stimulus-responsive nanocarriers enable precise targeting and controlled release in inflammatory microenvironments. Nanoparticles, liposomes, hydrogels, and microspheres enhance drug penetration and retention, overcoming rapid clearance. These innovations improve delivery efficiency and prolong the therapeutic effects, thereby advancing cartilage regeneration and personalized treatment. This review examines novel intra-articular delivery strategies to expedite the clinical translation of nanomaterial-based therapies.
