Nanocarrier-enabled Gene and Nucleic Acid Therapeutics for Rheumatoid Arthritis: Advances, Translational Evidence, and Regulatory Challenges.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovial inflammation, cartilage degradation, and bone erosion. Conventional diseasemodifying antirheumatic drugs and biologics, although effective in many patients, are limited by systemic toxicity, variable responsiveness, and loss of efficacy over time. Recent advances in nanomedicine have enabled the development of non-viral and viral gene delivery platforms designed to modulate pathogenic pathways at the molecular level. Non-viral nanocarriers, including liposomes, polymeric nanoparticles, lipid nanoparticles, and hybrid systems, have demonstrated efficient delivery of siRNA, antisense oligonucleotides, and mRNA targeting key inflammatory mediators such as TNF-α and NF-κB, resulting in significant disease attenuation in preclinical RA models. Viral vectors, particularly adeno-associated viruses and lentiviruses, provide sustained intra-articular gene expression but raise concerns related to immunogenicity and long-term safety. Emerging gene-editing strategies, notably CRISPR/Cas-based approaches, offer the potential to precisely and durably modulate disease-driving genes. But clinical translation is restricted by off-target effects, ethical considerations, and regulatory barriers. Collectively, the available evidence underscores both the therapeutic potential and inherent complexity of nanocarrier-mediated gene and nucleic acid therapies for RA, emphasizing the necessity for optimized delivery strategies, rigorous safety assessments, and biomarker-guided patient stratification to achieve successful clinical translation. This review comprehensively covered various gene delivery modalities, including non-viral and viral vectors, and gene editing (CRISPR/Cas) approaches. At the end, preclinical and clinical evidence, along with extensive case studies, for RA treatment were also highlighted. This review also outlined challenges and future directions in the management of arthritis.