Self‐Assembled Bifunctional Exosomes Simplify Chondrocyte‐Targeted Sustained‐Release Systems in Decellularized Cartilage Microgels for Synergistic Osteoarthritis Therapy

Abstract Stem cell‐derived exosomes represent a potential treatment for osteoarthritis (OA), but their effectiveness is limited by non‐specific targeting and rapid clearance in vivo. Although cartilage‐targeted exosomes with sustained‐release delivery systems have recently been developed, their intricate and lengthy fabrication procedures require specialized equipment and technical proficiency, risking damage to the integrity of exosomes and thereby limiting their clinical and commercial potential. This study presents a self‐assembled bifunctional exosome strategy for the simple fabrication of an enhanced chondrocyte targeting and sustained release system within decellularized cartilage‐based (HECM) microgels for intra‐articular OA treatment. The self‐assembly of chondrocyte‐targeting and collagen II‐binding peptide‐based polymer chains onto the exosome surface enhances their chondrocyte binding and facilitates stable encapsulation within HECM microgels, which mimic the native environment, nourishing chondrocytes with exosomes to boost viability and matrix production of OA chondrocytes while inhibiting hypertrophy in vitro. In an OA rat model, the system extends exosome retention, promotes cartilage repair, and slows disease progression via PI3K/AKT pathway modulation. This self‐assembly approach, which endows exosomes with enhanced chondrocyte targeting and stable loading within HECM microgels, offers a more practical and synergetic therapeutic strategy for managing OA.