Abstract RNA interference (RNAi) is an evolutionary conserved mechanism for post transcriptional control of protein expression in which short double-stranded RNA target specific messenger RNA (mRNA) for degradation, thus inhibiting protein translation. siRNA has great potential to revolutionize medicine by enabling highly specific and efficient silencing of proteins involved in disease pathogenesis. Despite nearly 25 year of effort dedicated to translating siRNA into a clinically relevant therapeutic, minimal clinical success has been achieved to date for broad-based application due to lack of effective delivery technologies. Last year, FDA approved first-ever siRNA drug developed by Alnylam® for an orphan disease, transthyretin-mediated amyloidosis. However, lipidic based siRNA delivery technology employed by Alnylam® limits the applications to liver diseases or treatments targeting liver involvement. Therefore, alternative delivery technologies are required to fully unleash the potential of siRNA and other nucleotides, e.g. mRNA, as effective therapeutics. To address these unmet medical needs, we developed a new peptide (p5RHH)-based nucleotide delivery platform, which can deliver nucleotides (e.g. siRNA and mRNA) to sites of inflammation in vivo after systemic administration. This delivery platform protects nucleotides in the blood stream and enables nucleotide endosomal escape for cytoplasmic delivery. The beneficial therapeutic effects have been demonstrated in preclinical animal models of atherosclerosis, necrotizing enterocolitis, pancreatic cancer, lung cancer, metastatic ovarian and uterine cancers, post traumatic osteoarthritis, and rheumatoid arthritis. In addition, this technology is patented and ready for commercial development. For product development, we will focus on anti-inflammatory treatment (anti-NFkB p5RHH-p65 siRNA nanoparticles) for rheumatoid arthritis, which is a chronic and debilitating inflammatory arthropathy. More than 1.3 million Americans suffer from rheumatoid arthritis. The global drug market for rheumatoid arthritis is expected to reach $30.7 billion dollars by 2025. We have demonstrated that p5RHH-p65 siRNA nanoparticles delivered intravenously effectively silence the expression of p65 (i.e., canonical NF-kB) and suppress a broad array of downstream cytokine effectors in a mouse rheumatoid arthritis model of collagen antibody-mediated inflammation. Consequently, arthritis is mitigated with minimal off-target molecular effects. The ultimate objective of this proposed work is to further develop p5RHH delivery platform into a clinical product for rheumatoid arthritis by targeting CD44 with following two specific aims. In the Specific Aim 1, we will establish an integrated and rapid hyaluronic acid coating process for the p5RHH-p65 siRNA nanoparticles that will enable molecular targeting via CD44, which is highly abundant in joint synovium of rheumatoid arthritis patients. In Specific Aim 2, we will test the best ...