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Small interfering RNA (siRNA) has emerged as a potent regulator of gene expression, with the potential to treat a variety of previously “undruggable” diseases. However, its clinical translation has been limited due to short circulation half-life, degradation by nucleases, and poor cytosolic delivery. To address these issues, we optimized the design of a novel hybrid PLGA and endosomolytic polymer (DMAEMA-co-BMA) core nanoparticle with a lipid-PEG corona for the delivery of siRNA. The optimized system showed high stability, cell uptake, and endosomal escape ability. These attributes result in delivery of the siRNA and gene silencing activity in vitro, with optimal activity achieved by tuning the nanoparticle core polymers. The optimized NP was tested as a therapeutic for osteoarthritis (OA), a chronic degenerative disease of the joint with no available disease-modifying drugs. Optimized nanoparticles were loaded with siRNA against MMP13, a key protease driving cartilage degeneration in OA. In a murine, repeat-loading disease model, our nanoparticles demonstrated 28 days of siRNA joint retention, MMP13 silencing activity 14 days following a single IA injection, and a reduction in pain sensitivity. These results indicate that our optimized nanoparticle effectively facilitated MMP13 silencing and led to functional improvements in diseased mice, prompting further studies into the ability of this system to treat OA.