Virus-inspired lipopeptide-derived nucleic acid delivery to cartilage for osteoarthritis therapy

Cartilage-targeted gene therapy is promising for osteoarthritis (OA) treatment, though its potency critically depends on the effectiveness of delivery vectors. Here, we modularly develop a series of non-pathogenic, virus-inspired lipopeptide-based nanoparticles (VPN) tailored to deliver nucleic acids to cartilage. The cationic moiety of lipopeptide with variable arginine and histidine residues is the key functional component, and screened by in vitro performance. The optimized VPN-2 with a moiety of -[(R)₅-(H)₄]₂- facilitates sufficient endocytosis and effective lysosomal escape, achieving about 2.5-fold improvement in transfection potency over conventional lipid nanoparticles. To address the tradeoff between penetration and retention within articular cartilage, si-VPN-2 is further formulated into ROS-responsive nano-in-gel system, which turns out to alleviate cartilage degeneration in surgical ACTL mice, and further synergizes with methylprednisolone to implement superior joint protection in PTOA mice. Our study underscores the platform's potential of VPN as cartilage-targeted RNA delivery vector for innovative OA therapy.