A Combinatorial mRNA Therapy for Treating Rheumatoid Arthritis and Osteoarthritis by Inhibiting Inflammation and Promoting Cartilage Regeneration

Abstract Rheumatoid arthritis (RA) and osteoarthritis (OA) are debilitating joint disorders with distinct etiologies but share common pathological features of chronic inflammation and progressive cartilage damage. Current therapeutic options are largely palliative and yet fail to achieve desired effect. In this study, we developed a combinatorial mRNA therapy using a rationally engineered lipid nanoparticle (LNP) containing a novel ionizable lipid for enhanced cartilage penetration upon intra-articular administration. This LNP co-delivers mRNAs encoding two complementary therapeutic proteins: interleukin-1 receptor antagonist (IL-1Ra) for inflammation attenuation and a C-terminal truncated derivative of angiopoietin-like 3 (ANL3) for cartilage regeneration. In pre-clinical models including collagen-induced arthritis mice, TNF-transgenic mice with spontaneous RA and destabilization of medial meniscus (DMM) surgical OA model, this “one-shot” combinatorial therapy significantly ameliorated disease severity, reduced synovitis and bone erosion, and potently promoted the regeneration of hyaline-like cartilage. Mechanistically, transcriptomic profiling of joint specimens revealed that the combinatorial therapy concurrently suppressed inflammatory pathways and extracellular matrix degradation pathways, meanwhile upregulating anabolic genes facilitating chondrogenesis. Collectively, our study establishes a versatile and synergistic mRNA therapy that offers a potent disease-modifying immunomodulatory strategy capable of addressing the long-standing unmet needs in arthritis treatment. Competing Interest Statement A.L. holds patent on the novel ionizable cationic lipid FS01. All other authors declare no conflict of interest.