Cartilage–targeting and Autophagy–activating of A Lubricin–inspired Polyzwitterion for Osteoarthritis Therapy

Abstract

Abstract Osteoarthritis is characterized by the progressive degradation of cartilage matrix and a deficiency in lubrication. This degeneration is exacerbated by the overexpression of inflammatory cytokines and free radicals. To address these challenges, inspired by lubricin that dominates cartilage lubrication, we synthesized a novel collagen type II (Col II)–binding peptide conjugated zwitterionic polymer (PSB–b–PColBP, PSP). Capitalizing on its targeted affinity to cartilage (–6.41 kcal/mol), PSP contributed to durable boundary lubrication (COF < 0.013) and remarkable enzyme–resistance (~ 100%) against matrix degradation. Additionally, PSP activates autophagy to mitigate oxidative stress. PSP preserved the chondrocytes’ ability to secrete cartilage matrix in inflammatory microenvironments through PI3K–Akt/NF–κB signaling pathway. In OA animal models, PSP inhibited osteophytes formation and reduced inflammation response, exhibiting therapeutic effect comparable to most drug–loaded systems. This study underscores the potential of the cartilage–targeting polyzwitterions for the clinical OA therapy.