Metal–Organic Framework-Integrated Nanoplatform Orchestrates Osteochondral-Synovial Homeostasis for Osteoarthritis Therapy
Hongwei Shao, Shunxiang Xu, Fanchu Zeng, Zheyu Jin, Xiongfa Ji, Zhengming Shan, Jingliang Kang, Qinyu Tian, Shian Zhang, Zhinan Mao, Yu Zhang, Jiankun Xu, Wenxue Tong, Ling Qin
Abstract
Osteoarthritis (OA) remains a formidable clinical challenge due to the intricate interplay of cartilage degradation, synovitis, and subchondral bone remodeling. Clinical intra-articular therapies are hindered by rapid drug clearance, inadequate cartilage penetration, and a lack of strategies targeting multifactorial pathogenesis. Herein, we engineered a hybrid nanoplatform for multiaction therapeutics by integrating boundary lubrication and “osteochondral-synovial synergistic effect.” The kartogenin (KGN)-loaded Mg/Zn-based metal–organic framework (Mg-ZIF) core, encapsulated within a cartilage affinity peptide-conjugated lubricant liposome (CAP-Lipo) shell, resulted in the CAP-Lipo@KGN@Mg-ZIF (CLKM) nanoplatform. This design synergistically achieved enhanced chondrocyte uptake, deep cartilage penetration, and prolonged joint retention. CLKM suppressed chondrocyte apoptosis and catabolic metabolism via diverse signaling pathways. Mg 2+ /Zn 2+ released from CLKM reprogrammed synovial macrophages toward a reparative phenotype, mitigating inflammation-driven cartilage matrix degradation and inhibiting osteoclastogenesis. Furthermore, KGN cooperated with the ionic microenvironment to enhance stem cell recruitment and chondrogenesis, driving structural cartilage repair. In surgery-induced OA mice, CLKM effectively preserved cartilage integrity, reduced synovitis, normalized subchondral bone remodeling, and restored gait symmetry. In loading-induced post-traumatic OA (PTOA) mice, a single intra-articular injection of CLKM counteracted PTOA progression. This study establishes CLKM as a versatile nanoplatform that orchestrates chondroprotection, immunomodulation, and tissue remodeling, disrupting the vicious cycle and offering a promising strategy for OA management.