A synergistic strategy involving reverse-adaptation and engineered MSC exosomes against ferroptosis in osteoarthritis

Osteoarthritis (OA) progression is driven by persistent oxidative stress and ferroptosis, which erode chondrocyte viability and extracellular matrix integrity. Although mesenchymal stem cell-derived exosomes (MSC-EXO) hold regenerative promise, their native cargo lacks the adaptability to withstand such a hostile microenvironment, limiting therapeutic efficacy. Here, we demonstrated a synergistic strategy involving reverse-adaptation and engineered MSC exosomes against ferroptosis in osteoarthritis. Firstly, the reverse-adaptation strategy in which OA-like oxidative stress was harnessed to precondition MSCs, thereby identifying miR-142a-3p as a key therapeutic mediator in tert-butyl hydroperoxide (TBHP)-modified exosomes (T-EXO). Subsequently, we engineered MSC-derived exosomes via miR-142a-3p electroporation (EXO^miR-142a-3p) with unique anti-ferroptosis and antioxidative properties. EXO^miR-142a-3p were markedly enriched with miR-142a-3p, which directly targeted the GSK3β/Nrf2/SLC7A11 axis to suppress ferroptosis and reactive oxygen species (ROS) accumulation. Compared to naive EXO, EXO^miR-142a-3p exhibited superior protection against cartilage matrix degradation and significantly slowed OA progression in a murine model. By integrating these engineered exosomes into a biodegradable, cartilage-targeted, and lubricious microsphere platform, we achieved sustained, site-specific delivery that amplified therapeutic durability and efficacy. This platform robustly mitigated extracellular matrix (ECM) degradation, ferroptosis, and oxidative stress in vitro, and conferred significant cartilage protection in a destabilization of medial meniscus (DMM)-induced OA model via efficient, prolonged intra-articular release. Collectively, this innovative approach not only provides potent cartilage protection in preclinical models but also establishes a paradigm for precision, microenvironment-adaptive regenerative therapies for OA and other degenerative diseases.