Abstract Osteoarthritis (OA) is one of the world’s leading causes of disability. About ~27 million adults in the U.S. have symptomatic OA and suffer from chronic pain for several decades. Current clinical management of OA is entirely palliative, and the definitive end-stage management is total joint arthroplasty. Consequently, there exists an immediate and critical need to develop novel treatments that improve chronic pain and disability in OA. Intra-articular corticosteroids have shown benefit over placebo in OA across all ages due to their ability to reduce pain and mitigate joint inflammation. However, their efficacy is short-lived and is associated with dose- dependent deleterious effects. We recently reported that therapeutic microparticles with the active drug comprising near 100% of the particle’s matrix, i.e., no exogenous polymer, can be achieved via a gold- nanoparticle templating method. Using this approach, this proposal seeks to develop corticosteroid-derived microparticles for the intra-articular treatment of OA. We hypothesize that erodible particles that consist almost entirely of the active drug molecules (>90%) will offer a controlled release of corticosteroids locally in the diseased joint for an extended period, effectively reducing the pain and inflammation in OA while avoiding adverse side effects associated with high doses, multiple treatments, and the use of exogenous biodegradable polymers. Specifically, we will explore the fabrication of methylprednisolone succinate sodium salt (MPS) particles by modifying our novel metal-nanoparticle templating method, which we have demonstrated for generating composite bile salt particle that enables fine-tuned, controlled release of therapeutically active bile salt. We will first mechanistically uncover how the fabrication parameters affect MPS-drug particle formation, geometry, and erosion characteristics while also confirming long-term intra-articular retention (Aim 1). We will then evaluate the anti-inflammatory capacity of the generated corticosteroid microparticles in vitro using OA- relevant cell types, assessing modulation of inflammatory gene and protein expression. We will confirm that corticosteroid particles have minimal deleterious effects on chondrocyte viability, proliferation, and extracellular matrix maintenance (Aim 2.1). We will then evaluate the therapeutic efficacy of the novel corticosteroid microparticles to control inflammation and pain in vivo using a clinically relevant mouse model of joint injury- induced OA (Aim 2.2). Overall, the proposed work, if successful, can make transformative progress towards the clinical treatment of OA and other joint disorders by providing a more efficacious and longer-lasting intra- articular analgesic therapy.