3D Cryo‐Printed Hierarchical Porous Scaffolds Harmonized with Hybrid Nanozymes for Combinatorial Mitochondrial Therapy: Enhanced Diabetic Bone Regeneration via Micromilieu Remodeling

Regeneration of bone defects in diabetic patients has always been a significant challenge in clinical treatment. The pathologic diabetic micromilieu, characterized by mitochondrial dysfunction, excessive reactive oxygen species (ROS) accumulation, cellular senescence, and chronic inflammation, compromises innate bone healing capacity. 3D cryo‐printing technology is utilized in bone tissue engineering to fabricate hierarchical porous scaffolds that promote a conducive microenvironment for cellular adhesion, migration, proliferation, and nutrient exchange. Nanozymes are used as synthetic mimics of natural enzymes to scavenge ROS, addressing the limitations of natural antioxidative enzymes. To remodel the diabetic bone regeneration micromilieu, a 3D cryo‐printed polyaryletherketone with carboxyl groups (PAEK‐COOH) and 45S5 bioactive glass (BG) hierarchical porous scaffold (PBG scaffold), harmonized with hybrid nanozymes comprising SS31‐enhanced manganese dioxide (MnO2)‐ferritin biomimetic nanozyme (MF@S nanozyme), is developed for combinatorial mitochondrial therapy. The MF@S nanozyme specifically targets mitochondria to enhance mitochondrial function, scavenge ROS accumulated in mitochondria, and suppress mitochondrial ROS (mtROS) production, and thus rejuvenate aging cells, regulate macrophage polarization, and modulate differentiation of osteoblasts and osteoclasts. This 3D cryo‐printed PBG‐MF@S hierarchical porous scaffold combines with a combinatorial mitochondrial therapy system to remodel the diabetic micromilieu and presents a promising therapeutic approach for the regeneration of bone defects in diabetes. A 3D cryo‐printed PAEK‐COOH and BG hierarchical porous scaffold (PBG scaffold), combined with MF@S nanozymes, is developed for combinatorial mitochondrial therapy. The MF@S nanozyme effectively scavenges ROS, improves mitochondrial function, rejuvenates senescent cells, regulates macrophage polarization, promotes osteoblast differentiation, and inhibits osteoclast differentiation. This approach shows potential for bone defect regeneration in diabetes.