Biomimetic hydrogel delivers engineered exosomes to attenuate cell senescence by AKG-mediated mitochondrial function restoration for osteoarthritis

Osteoarthritis (OA) is a common chronic degenerative joint disease. The disruption of intracellular homeostasis driven by chondrocyte senescence represents a major challenge in current clinical management of OA. Herein, we developed a mitochondrial function‑modulating strategy to disrupt the oxidative stress–inflammation–senescence network in osteoarthritic chondrocytes. In this approach, scutellarin was loaded into stem cell‑derived exosomes (Exosomes–Scutellarin, ES) to mitigate oxidative stress‑induced mitochondrial damage and exert anti‑inflammatory effects. The ES were further modified with macrophage membranes to form MES nanoparticles, enhancing their targeting capability to inflammatory sites. The MES nanoparticles were then encapsulated in a sodium alginate–hyaluronic acid hydrogel, yielding a multifunctional composite hydrogel (Sodium alginate −Hyaluronic acid hydrogel @Macrophage membrane −Exosomes–Scutellarin, SH@MES). SH@MES not only suppressed oxidative stress but also prolonged nanoparticle retention within the joint cavity. In vitro results showed that Macrophage membrane–Exosomes–Scutellarin (MES) enhanced chondrocyte uptake and alleviated senescence through α‑ketoglutarate (AKG)‑mediated regulation of mitochondrial function. In vivo experiments revealed that SH@MES exhibited excellent joint retention and cartilage repair capacity in a mouse OA model, effectively delaying disease progression. In summary, SH@MES disrupts the oxidative stress–inflammatory–senescence network in chondrocytes via AKG‑driven modulation of mitochondrial function, offering a promising therapeutic strategy for osteoarthritis.