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. Mg2+/Zn2+ 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.
Keywords: cartilage regeneration; kartogenin delivery; lubrication; macrophage polarization; metal−organic frameworks; osteoarthritis.