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Osteoarthritis (OA) is a chronic joint disease characterized by progressive degeneration of articular cartilage. A challenge in the development of disease-modifying drugs is effective delivery to chondrocytes. The unique structure of the joint promotes rapid clearance of drugs through synovial fluid, and the dense and avascular cartilage extracellular matrix (ECM) limits drug penetration. Here, we show that poly(lactide-co-glycolic acid) nanoparticles coated in chondrocyte membranes (CM-NPs) were preferentially taken up by rat chondrocytes ex vivo compared with uncoated nanoparticles. Internalization of the CM-NPs was mediated primarily by E-cadherin, clathrin-mediated endocytosis, and micropinocytosis. These CM-NPs adhered to the cartilage ECM in rat knee joints in vivo and penetrated deeply into the cartilage matrix with a residence time of more than 34 days. Simulated synovial fluid clearance studies showed that CM-NPs loaded with a Wnt pathway inhibitor, adavivint (CM-NPs-Ada), delayed the catabolic metabolism of rat and human chondrocytes and cartilage explants under inflammatory conditions. In a surgical model of rat OA, drug-loaded CM-NPs effectively restored gait, attenuated periarticular bone remodeling, and provided chondroprotection against cartilage degeneration. OA progression was also mitigated by CM-NPs-Ada in a canine model of anterior cruciate ligament transection. These results demonstrate the feasibility of using chondrocyte membrane–coated nanoparticles to improve the pharmacokinetics and efficacy of anti-OA drugs. Editor's summary: Osteoarthritis (OA) lacks effective disease-modifying treatments partially because of the difficulty of delivering drugs to dense and avascular cartilage tissue. Here, Deng et al. disguised drug-carrying nanoparticles with chondrocyte membranes to increase the interaction of the nanoparticles with cartilage. These membrane-coated nanoparticles retained critical chondrocyte proteins that supported cell and matrix interactions in explanted rat and human cartilage. These nanoparticles were retained in rat knee in vivo for at least 34 days. In rat and canine models of injury-induced OA, release of a Wnt-pathway inhibitor from these nanoparticles improved cartilage and subchondral bone morphology. These findings support the further development of chondrocyte-mimicking particles for cartilage drug delivery and OA therapy. —Molly Ogle [ABSTRACT FROM AUTHOR]