Advanced RNA Therapeutics: "Molecular Scalpels" for Cartilage Microenvironment Remodeling

Osteoarthritis (OA) is a debilitating degenerative joint disease urgently requiring disease-modifying therapies. Although multimodal RNA therapeutics (e.g., siRNA, miRNA, and mRNA) exhibit immense potential in reprogramming the complex OA pathological network, their clinical translation remains severely impeded by the hostile intra-articular microenvironment and rapid nucleolytic degradation. This review comprehensively evaluates the evolutionary trajectory of RNA delivery systems tailored for OA, advancing from conventional lipid nanoparticles (LNPs) and natural exosomes to sophisticated hierarchical platforms, including lipo-exosome hybrids, stimuli-responsive metal-organic frameworks (MOFs), and injectable hydrogels. These engineered vectors successfully breach cartilaginous barriers, enabling deep tissue penetration, prolonged joint retention, and microenvironment-responsive payload release. Finally, by synergizing advanced biomaterial engineering with precision genetic modulation, we outline the current translational bottlenecks and highlight future trajectories—such as the emerging role of artificial intelligence in rational nanocarrier design—to develop next-generation, dynamically responsive RNA therapeutics for authentic joint microenvironment remodeling.