A motion-activated skeletal “Pacemaker” for systemic bone remodeling via oral piezoelectric microspheres

The loss of endogenous bioelectrical rhythms in bone is a critical driver of osteoporosis initiation and progression. Reconstructing bioelectrical rhythms synchronized with mechanical stimulation is critical for restoring bone homeostasis. Here, we propose a motion-activated skeletal “bioelectrical pacemaker” strategy that microfluidically encapsulates alendronate-modified BaTiO 3 piezoelectric nanoparticles (BTO@ALN) within chitosan/alginate core–shell hydrogel microspheres, enabling gastric protection, pH-responsive intestinal release, and noninvasive oral delivery with systemic skeletal enrichment. Upon skeletal enrichment, the piezoelectric units compensate for impaired electrophysiological responsiveness in osteoporotic bone and are activated by physiological mechanical stimuli during daily motion to generate movement-synchronized dynamic bioelectrical signals. This process reconstructs endogenous bone bioelectrical rhythms systemically, thereby restoring bone homeostasis. Experimentally, BTO@ALN exhibited 6.8-fold higher skeletal accumulation than controls; oral administration led to a 52% increase in bone piezoelectric performance within 24 h, accompanied by concurrent suppression of osteoclast activity and promotion of osteogenesis. When combined with low-intensity exercise, motion-triggered piezoelectric output further amplified therapeutic efficacy, resulting in a 2.4-fold increase in osteogenesis and a 1.5-fold stronger suppression of bone resorption. Collectively, this closed-loop strategy integrating oral delivery, bone-targeted enrichment, and motion-synchronized electrical activation systematically re-establishes endogenous bone bioelectrical rhythms, introducing a strategy for osteoporosis based on electrophysiological regulation of bone.