Musculoskeletal health is vital across species for overall well-being and quality of life. Despite anatomical differences, both humans and dogs suffer from acute injuries and idiopathic joint disease leading to osteoarthritis (OA) and reduced quality of life. Current interventions fail to fully replicate native tissue properties while also addressing joint-wide inflammation that perpetuates detrimental catabolic feedback loops. This thesis focuses on the sustained delivery of biologics to interrupt this cycle, targeting both tissue-specific (meniscus) and joint-wide (synovial) tissues. First, we explore how inflammation impacts meniscal cell behavior and show that proinflammatory cytokines impede cell migration and alter mechanosensation and that an interleukin receptor therapeutic (IL-1Ra) can rescue this aberrant behavior. To implement this finding, mechano-activated microcapsules (MAMCs) are then used for targeted delivery of IL-1Ra and TGF-β to meniscus tissue in vivo to promote matrix formation in large animal models, suggesting potential for clinical application. We then expand our focus to address joint-wide targets for inflammation, focusing first on the differences between humans and dogs in OA treatment and avenues available to increase species cross-talk when evaluating new biologics as OA interventions. A retrospective study on synovitis in dogs with cruciate ligament tears further reveals parallels with human patients and underscores the importance of addressing synovitis as a key player in joint pain after acute injury. Then, histological, mechanical, and transcriptional analyses of synovium from affected dogs identify key pathways for therapeutic intervention, with IL6 and IL1 receptor therapeutics showing promise in mitigating inflammation. These findings are then translated to a pilot clinical trial testing the efficacy of MAMC-encapsulated IL-1Ra in canine patients presenting to the clinic with cruciate ligament disease, demonstrating safety and potential efficacy. Together, these studies advance our understanding of tissue-specific and jointwide interventions for diarthrodial joint injuries, paving the way for improved musculoskeletal health outcomes in both human and veterinary patients.