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The periosteum plays a vital role in the regeneration of critical‐size bone defects and highly comminuted fractures, promoting the differentiation of osteoblasts, accelerating the reconstruction of the vascular network, and guiding bone tissue regeneration. However, the materials loaded with exogenous growth factors are limited by the release and activity of the elements. Therefore, the material structure must be carefully designed for the periosteal function. Here, a self‐adaptive biomimetic periosteum strategy is proposed, which is a novel interpenetrating double network hydrogel consisting of diselenide‐containing gelatin and calcium alginate (modified natural collagen and polysaccharide) to enhance the stability, anti‐swelling, and delayed degradation of the hydrogel. The diselenide bond continuously releases nitric oxide (NO) by metabolizing endogenous nitrosated thiols (RSNO), activates the nitric oxide‐cycle guanosine monophosphate (NO‐cGMP) signal pathway, coordinates the coupling effect of angiogenesis and osteogenesis, and accelerates the repair of bone defects. This self‐adaptive biomimetic periosteum with the interpenetrating double network structure formed by the diselenide‐containing gelatin and calcium alginate has been proven to be safe and effective in repairing critical‐size bone defects and is expected to provide a promising strategy for solving clinical problems. The double network hydrogel has the ability of rapid gelation and can balance the mechanical strength and toughness. The diselenide bond structure in the artificial periosteum can catalyze the endogenous S‐nitrosated thiols (RSNO) to produce nitric oxide (NO), which is conducive to adhesion, proliferation, osteoblastic differentiation, and angiogenesis, thus inducing the healing of critical‐size bone defects.

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.

Responsive Microspheres In article 2302475by Huilin Yang, Yong Xu, Yijian Zhang, Xuesong Zhu, and co‐workers, a microenvironment responsive hydrogel microsphere is developed to rebalance BCL2/BAX‐cytochrome c (mtApoptosis) and PINK1/Parkin‐LC3B‐P62 (mitophagy) through activation of the mitochondrial guardian SIRT3. Restoring mitochondrial homeostasis proves effective in rescuing extracellular matrix disintegration and restraining articular cartilage degeneration, thereby providing a novel organelle‐oriented strategy for treating osteoarthritis.