Glutamine‐Modified Ionizable Lipid Nanoparticles Deliver FGF18‐mRNA to Alleviate Cartilage Degeneration in Osteoarthritis

ABSTRACT Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage breakdown, metabolic disorder, and pain. Current therapies provide only symptomatic relief, while cartilage has limited intrinsic repair capacity. Here, we developed glutamine‐modified ionizable lipid nanoparticles (GLNP) for intra‐articular delivery of FGF18 mRNA. GLNP showed uniform particle size and a favorable polydispersity index, enabling complete RNA encapsulation and protection against degradation. Compared with unmodified lipid nanoparticles (LNP), GLNP achieved efficient lysosomal escape, deep cartilage penetration, and enhanced chondrocyte uptake. In vitro, GLNP‐mediated FGF18 mRNA delivery increased anabolic marker expression and reduced catabolic and senescence markers in chondrocytes, while glutamine release further enhanced metabolic synergy. In a surgically induced OA mouse model, intra‐articular GLNP‐FGF18 improved gait parameters and attenuated cartilage degeneration. It also suppressed synovial inflammation, reduced osteophyte formation, and preserved cartilage matrix integrity in both early and delayed intervention settings. Mechanistically, the therapeutic effect was associated with PRG4 upregulation, PI3K‐Akt‐mTOR signaling modulation, and autophagy restoration. Overall, GLNP‐FGF18 mRNA reversed chondrocyte catabolic and senescent phenotypes and restored joint homeostasis by combining cartilage penetration, chondrocyte affinity, and metabolic regulation, offering a promising synergistic gene therapy for OA.