Retuning Mitochondrial Apoptosis/Mitophagy Balance via SIRT3‐Energized and Microenvironment‐Modulated Hydrogel Microspheres to Impede Osteoarthritis

Full‐range therapeutic regimens for osteoarthritis (OA) should consider organs (joints)‐tissues (cartilage)‐cells (chondrocytes)‐organelles cascade, of which the subcellular mitochondria dominate eukaryotic cells' fate, and thus causally influence OA progression. However, the dynamic regulation of mitochondrial rise and demise in impaired chondrocytes and the exact role of mitochondrial metronome sirtuins 3 (SIRT3) is not clarified. Herein, chondrocytes are treated with SIRT3 natural agonist dihydromyricetin (DMY) or chemical antagonist 3‐TYP, respectively, to demonstrate the positive action of SIRT3 on preserving cartilage extracellular matrix (ECM). Molecular mechanical investigations disclose that SIRT3‐induced chondroprotection depended on the repression of mitochondrial apoptosis (mtApoptosis) and the activation of mitophagy. Inspired by the high‐level matrix proteinases and reactive oxygen species (ROS) in the OA environment, by anchoring gelatin methacrylate (GelMA) and benzenediboronic acid (PBA) to hyaluronic acid methacrylate (HAMA) with microfluidic technology, a dual‐responsive hydrogel microsphere laden with DMY is tactfully fabricated and named as DMY@HAMA‐GelMA‐PBA (DMY@HGP). In vivo injection of DMY@HGP ameliorated cartilage abrasion and subchondral bone sclerosis, as well as promoted motor function recovery in post‐traumatic OA (PTOA) model via recouping endogenous mtApoptosis and mitophagy balance. Overall, this study unveils a novel mitochondrial dynamic‐oriented strategy, holding great promise for the precision treatment of OA. Starting from the mitochondria in chondrocytes, activation of SIRT3 suppressed mtApoptosis via BCL2/BAX‐cytochrome c release‐apoptosome arrest but promoted mitophagy via the PINK1/Parkin‐LC3B‐mitophagosomal complex, thus impeding ECM degradation. DMY@HGP hydrogel microspheres, responding to OA‐specific ROS and degrading micro‐milieu, is able to ameliorate joint degeneration and improve functional motion by full‐range mitochondria‐chondrocytes‐cartilage precision modulation.