Biomimetic Mitochondrial Vesicles Delivered by Lubricative Hydrogel Microspheres Enable Cartilage Repair in Osteoarthritis

ABSTRACT Mitochondrial dysfunction in chondrocytes and the loss of joint lubrication are increasingly recognized as key pathological drivers of functional deterioration in osteoarthritis (OA). However, the rational design of multifunctional biomaterials capable of concurrently regulating bioenergetic metabolism and the joint mechanical microenvironment remains highly challenging. Inspired by the natural process of mitochondrial‐derived vesicles (MDVs) formation, we rationally employed a gradient extrusion‐based strategy to fabricate biomimetic mitochondrial membrane vesicles (BMMVs), which enable efficient cartilage penetration and intrinsic mitochondrial targeting. Upon loading with the Sirtuin 3 (Sirt3) activator dihydromyricetin (DMY), the resulting DMY‐BMMVs effectively restore inflammation‑induced mitochondrial dysfunction and reprogram chondrocyte metabolism homeostasis. Furthermore, drawing inspiration from the hydration brush architecture of lubricin, PLL‑g‑PEG (polylysine‐g‐polyethylene glycol) is electrostatically assembled onto methacrylated hyaluronic acid (HAMA) microspheres to construct a bioinspired PEG brush interface. This lubricating microsphere system simultaneously serves as an intra‐articular delivery depot for DMY‐BMMVs, enabling sustained vesicle release while reconstructing the joint lubrication microenvironment. In vivo studies demonstrated that this integrated system markedly enhances cartilage regeneration, alleviates OA‐associated pain, and restores joint mobility. Overall, this work establishes a multifunctional materials‐driven platform that synergistically integrates mitochondrial‐targeted metabolic regulation with bioinspired interfacial lubrication, offering a new paradigm for OA treatment from a biomaterials engineering perspective.