Mitochondria-targeted MXene-based nanozymes promote mitophagy and inhibit mtDNA-triggered cGAS/STING inflammation in osteoarthritis.

Abstract

Osteoarthritis (OA) is a prevalent and debilitating joint disease driven by progressive cartilage degradation, mitochondrial dysfunction, and chronic inflammation. In this study, we introduced MS@PMXene-TK, an innovative, mitochondria-targeted nanozyme designed for cartilage repair by addressing these key pathological features. This nanozyme platform uniquely integrated a chondro-inductive peptide (SPPEPS)-loaded, polydopamine (PDA)-modified MXene core (S@PMXene) with a reactive oxygen species (ROS)-responsive thioketal-linked polyethylene glycol (PEG-TK) shell and a mitochondria-targeting peptide (MTP-131), enabling precise and responsive therapeutic intervention at the subcellular level. <i>In vitro</i> and <i>in vivo</i> analyses demonstrated that MS@PMXene-TK effectively scavenged mitochondrial ROS within chondrocytes, acting as a "cruise missile," which led to restoration of mitochondrial membrane potential and promotion of mitophagy. This cascade mitigated mtDNA leakage and subsequent activation of the cGAS/STING pathway, a critical inflammatory driver in OA. Concurrently, sustained release of SPPEPS enhanced chondrogenic marker expression and extracellular matrix synthesis, while alleviating macrophage-mediated inflammatory responses, further modulating the inflammatory microenvironment. In an anterior cruciate ligament transection (ACLT)-induced OA mouse model, intra-articular administration of MS@PMXene-TK significantly improved cartilage protection and subchondral bone integrity. These findings establish the potential of this targeted, multi-modal nanozyme strategy to disrupt intertwined pathologies of oxidative stress and inflammation in OA, offering a promising avenue for OA treatment.