1Osteoarthritis (OA) is a debilitating and prevalent chronic disease, but there are no 2 approved disease modifying OA drugs (DMOADs), only pharmaceuticals for pain management. 3 OA progression, particularly for post-traumatic osteoarthritis (PTOA), is associated with 4 inflammation and enzymatic degradation of the extracellular matrix. In particular, Matrix 5Metalloproteinase 13 (MMP13) breaks down collagen type 2 (CII), a key structural component of 6 cartilage extracellular matrix, and consequently, matrix degradation fragments perpetuate 7 inflammation and a degenerative cycle that leads to progressive joint pathology. Here, we tested 8 targeted delivery of endosome-escaping, MMP13 RNA interference (RNAi) nanoparticles (NPs) 9 as a DMOAD. The new targeting approach pursued here deviates from the convention of targeting 10 specific cell types (e.g., through cell surface receptors) and instead leverages a monoclonal 11 antibody (mAbCII) that targets extracellular CII that becomes uniquely accessible at early OA 12 focal defects. Targeted mAbCII-siNPs create an in situ NP depot for retention and potent activity 13 within OA joints. The mAbCII-siNPs loaded with MMP13 siRNA (mAbCII-siNP/siMMP13) 14 potently suppressed MMP13 expression (95% silencing) in TNFa-stimulated chondrocytes in 15 vitro, and the targeted mAbCII-siNPs had higher binding to trypsin-damaged porcine cartilage 16 than untargeted control NPs. In an acute mechanical injury mouse model of PTOA, mAbCII-17 siNP/siMMP13 achieved 80% reduction in MMP13 expression (p = 0.00231), whereas a non-18 targeted control achieved only 55% silencing. In a more severe, PTOA model, weekly mAbCII-19 siNP/siMMP13 long-term treatment provided significant protection of cartilage integrity (0.45+/-20 .3 vs 1.6+/-.5 on the OARSI scale; p=0.0166), and overall joint structure (1.3+/-.6 vs 2.8+/-.2 on 21 the Degenerative Joint Disease scale; p<0.05). Intra-articular mAbCII-siNPs better protected 22 articular cartilage (OARSI score) relative to either single or weekly treatment with the clinical gold 23 Abstract Figure: PTOA targeted delivery of MMP13 siRNA to block disease progression.