<p>Osteoarthritis (OA) is a chronic degenerative arthritis with substantial global health and economic burden, especially intensified in recent year. The conventional therapeutics causes several systemic side effects <i>via</i> prolonged uses of oral or topical administration. To overcome the limitations of conventional therapeutics, lipid-based nanoparticles at localized site of administration represent a promising therapeutic approach for OA management, offering targeted drug delivery, enhanced bioavailability, and improved therapeutic outcomes. These nanosystems leverage their biocompatible lipid composition and nanoscale properties to overcome the significant challenges associated with conventional OA treatments. In this context, this comprehensive article summarizes the potential effectiveness of lipid-based delivery systems in OA management. The article initially summarizes the pathophysiology, role of inflammatory cytokines, matrix metalloproteinases, and lipid metabolism in OA management. The manuscript delves into the importance of lipid-based systems for therapeutic delivery and discusses various studies that summarize lipid-based delivery systems in preclinical settings for OA treatment, particularly focusing on the intra-articular administration of lipid-based nanoparticles in joint retention time, delayed lymphatic drainage, and electrostatic interactions with the extracellular matrix. The manuscript also enlisted a limited number of recent clinical trials and further assessed the safety profile of the localized administration of lipid-based delivery system in OA treatment. This manuscript is the first of its kind to compile and compare examples of lipid-based delivery systems against the existing literature focused on various delivery methods in OA management. This manuscript has been meticulously drafted, considering both the applications of first-generation lipid-based delivery systems in OA management and current innovative approaches.</p> Graphical abstract <p></p>