Mechano‐Electrical Coupling Scaffold Drives Bone Organoids Bioenergetic Reprogramming to Accelerate Bone Regeneration

ABSTRACT Critical‐sized bone defects remain a major clinical challenge in orthopedics and regenerative medicine. Bone organoid provided therapy potentials; however, current engineering strategies generally neglect the bioenergetic foundation and intrinsic mechano‐electrical coupling microenvironment of native bone tissue. Herein, we prepared a three‐dimensional native bone electromechanical niche‐mimicking mechano‐electrical coupling scaffold based on piezoelectric potassium sodium niobate and methacrylated gelatin. Experiments demonstrate that this scaffold establishes an enabling physiologically relevant mechanical–electrical microenvironment throughout organoid construction under dynamic mechanical stimulation, which markedly enhances osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs)and simultaneously endows the engineered organoids with robust pro‐angiogenic and pro‐lymphangiogenic paracrine functions, achieving efficient coordinated regeneration in a rat critical‐sized calvarial defect. RNA‐sequencing together with fluorescent staining proved that mechano‐electrical coupling signals activate the PIEZO1 channel to promote Ca 2+ influx into the cytoplasm and simultaneously upregulate mitochondrial calcium uniporter (MCU) expression, thereby enhancing mitochondrial Ca 2+ . The increased mitochondrial Ca 2 + enrichment promoted tricarboxylic acid cycle enzyme activities and elevated cellular ATP production, which efficiently supports the functional maturation of bone organoids. Overall, this work establishes a bioenergetic engineering construction strategy for bone organoids with enhanced vascular/lymphatic system regeneration, providing both a conceptual framework and an engineering approach for organoid functional optimization and critical‐sized bone defect regenerative treatment.