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.

中文翻译：

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软骨细胞膜涂层纳米粒子促进药物保留并阻止大鼠和犬骨关节炎的软骨损伤

骨关节炎（OA）是一种慢性关节疾病，其特征是关节软骨进行性退化。开发缓解疾病药物的一个挑战是有效递送至软骨细胞。关节的独特结构促进药物通过滑液快速清除，致密且无血管的软骨细胞外基质（ECM）限制药物渗透。在这里，我们表明聚（丙交酯）共与未涂覆的纳米颗粒相比，涂覆在软骨细胞膜（CM-NP）上的纳米颗粒在离体时优先被大鼠软骨细胞吸收。CM-NP 的内化主要由 E-钙粘蛋白、网格蛋白介导的内吞作用和微胞饮作用介导。这些CM-NPs在体内粘附在大鼠膝关节的软骨ECM上，并深入渗透到软骨基质中，停留时间超过34天。模拟滑液清除研究表明，负载 Wnt 通路抑制剂 adavivint (CM-NPs-Ada) 的 CM-NP 可以延迟炎症条件下大鼠和人类软骨细胞和软骨外植体的分解代谢。在大鼠 OA 手术模型中，载药 CM-NP 有效恢复步态，减弱关节周围骨重塑，并提供软骨保护以防止软骨退化。在前交叉韧带横断的犬模型中，CM-NPs-Ada 也可以减轻 OA 的进展。这些结果证明了使用软骨细胞膜包被的纳米颗粒来改善抗 OA 药物的药代动力学和功效的可行性。