Advances in Injectable miRNA-Loaded Nanocomposite Hydrogel Systems for Cartilage Repair in KOA

Knee osteoarthritis (KOA) is a common degenerative joint disease characterized by irreversible cartilage injury, progressive tissue degeneration and compromised joint function. Conventional clinical treatments merely relieve symptoms rather than fundamentally repair damaged cartilage. As an innovative and promising therapeutic strategy, microRNA (miRNA)-based gene therapy modulates key pathogenic signaling pathways to improve core KOA pathological changes, including chondrocyte senescence, ECM degradation, synovial inflammation and aberrant subchondral bone remodeling. Nevertheless, the clinical application of bare miRNAs is greatly constrained by intra-articular biological barriers. Once delivered into the knee joint cavity, unprotected miRNAs are readily degraded by endogenous nucleases within synovial fluid, accompanied by off-target diffusion, undesired local inflammatory reactions, and rapid in-vivo clearance. Repeated injections are thus required to maintain effective drug concentration, which inevitably causes additional trauma to joint tissues and further compromises therapeutic performance. Injectable miRNA-nanocomposite hydrogel systems organically combine gene therapy, nanotechnology and biomaterial engineering, enabling localized intra-articular delivery, long-term sustained-release behaviour and lesion-oriented cartilage repair. Such biomaterial platforms are capable of remodelling the disordered intra-articular immune microenvironment and restoring subchondral bone homeostasis, so as to mitigate KOA-derived pathological lesions. Notwithstanding these promising advances, existing hydrogel formulations still face considerable bottlenecks in mechanical adaptability, cartilage-barrier penetration performance and long-term biosafety, which constitute major obstacles toward clinical translation. This review systematically summarizes the design strategies, functional modifications and repair mechanisms of these hydrogel systems, aiming to deepen mechanistic understanding, provide theoretical evidence for translational research, and promote the development of precise and individualized targeted therapies for KOA.