Osteoarthritis (OA) is a non-inflammatory degenerative joint disease affecting all joint structures, e.g. cartilage, bone and synovium. Early prevention of cartilage damage following a traumatic joint injury can potentially reduce the severity of OA disease progression. Systemic treatment modalities for OA are limited by systemic side effects and inability to reach therapeutic levels in articular cartilage. Owing to the involvement of a single or a few articular joints, OA is a disease amenable to local drug delivery. When delivered intra- articularly, small molecules and large polymers alike are rapidly taken up by the circulation resulting in short joint residence time. Nanocarrier drug delivery technology offers the potential to improve drug retention and facilitate cartilage tissue diffusion and chondrocytes uptake following intra-articular administration. The objective of this R15 application is to evaluate liposomal and solid nanoparticle formulation with surface functionalities that improves cartilage tissue retention and cellular uptake. The long-term goal is to delineate the necessary attributes of nanoparticles that make them of translational value as carriers of OA disease- modifying therapies. The central hypothesis of this application is that a nanocarrier with peptide surface modifications that facilitates cellular uptake and cartilage binding will show an improvement in joint residence time and cellular uptake compared to a similar nanocarrier that lacks these surface modifications. Three specific aims are used to test the central hypothesis as follows: 1) To evaluate cartilage retention, diffusion and chondrocytes uptake of cartilage-targeted nanoparticles using the bovine full-thickness articular cartilage plug model, 2) To evaluate cartilage retention and biodistribution of cartilage-targeted nanoparticle vehicle delivered intra-articularly in a rat model with or without ACL transection and 3) To evaluate the anti-apoptotic effect of Z- VAD-FMK, a pan-caspase inhibitor, loaded in a cartilage-targeted nanoparticle in an ACL transection rat model. The proposed work is innovative as it uses well-characterized models to identify cartilage-targeted nanocarriers with demonstrable enhanced cartilage retention and cellular uptake to accelerate the clinical development of candidate therapies via controlling joint tissue distribution and delivery. Expected outcomes are that we will successfully develop nanocarriers with surface modifications that result in enhanced cartilage tissue accumulation and joint residence time and can subsequently be utilized successfully to deliver an intra- cellular caspase inhibitor to provide disease-modifying anti-osteoarthritic effects. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health due to the impact of traumatic joint injury and osteoarthritis on the population's health and quality of life and the value this research brings to developing pharmaceutical formulations that can be successfully utilized in treatment of osteoarthritis. The segment of population mostly impacted by this research is patients with an ACL injury and patients with early osteoarthritis. The potential impact is major as it explores the potential for pharmaceutical nanocarriers loaded with OA treatments to enhance the beneficial effects of the treatments while minimizing the risk of systemic adverse effects.