PROJECT SUMMARY/ABSTRACT Osteoarthritis (OA) results from a combination of natural wear and tear associated with aging and/or unnatural mechanical loading on the joint. Patients who suffer a joint injury (e.g., ligament damage) have increased risk for early development of OA. Injury-related post-traumatic osteoarthritis (PTOA) often occurs in younger patients. PTOA and OA are both associated with articular cartilage erosion and other joint changes that cause pain and loss in quality of life. The available treatments only provide temporary pain relief. However, alleviation of pain only briefly masks the disease and does not halt or slow its progression. Progression of PTOA/OA to the point where joint replacement becomes necessary is almost inevitable for large joints because there are currently no disease-modifying osteoarthritis drugs (DMOADs) that can stop progression of or cure the disease. Loss of cartilage associated with OA and PTOA is driven by local upregulation of matrix metalloproteinases (MMPs). We propose that blocking the cartilage-degrading MMPs could stop the progression of PTOA/OA, improve quality of life, and reduce the need for joint replacement in afflicted patients. Pharmaceutical companies have previously tested drugs that can block the activity of MMPs, but these treatments have failed, primarily because their lack of specificity and lack of delivery approaches that localize the drug to the affected joint. We propose to develop intra-articularly injected bioadhesive nanoparticles for locally-retained delivery of short interfering RNA (bioad-si-NPs). The bioad-si-NPs will potently and specifically “knock down” specific MMPs to halt cartilage degradation in joints with OA or at risk of OA development (following injury). The mechanism of siRNA enables these molecules to be selective for specific MMPs, and the bioad-si-NPs are designed to be retained locally at the site of intra-articular delivery; both of these features contribute to our approach having reduced risk of off target side effects. We will test bioad-si-NPs in animal models of both PTOA and spontaneous OA and for inhibition of single or combinations of MMPs. In the setting of spontaneous OA, we will also test the value of initiating treatment at early versus more advanced stages of disease. This project is uniquely accessible through the interdisciplinary team with bioengineering expertise in intracellular biologic drug delivery nanotechnologies and RNA chemistry (Duvall), OA biology and animals models (Hasty), analysis of PTOA/OA animal model joint function/pain (Krug), and clinical care of OA patients (Crofford).