Bone-targeted SPIONs mimicking exercise-induced mechanical stimulation to activate mitophagy and suppress osteocyte senescence for senile osteoporosis therapy

Senile osteoporosis (SOP) is a highly prevalent age-related skeletal disorder, yet current management remains suboptimal. Exercise therapy is widely recognized as an effective non-pharmacological strategy to prevent and attenuate SOP, but its clinical utility is constrained in older individuals, underscoring the need for a safe, controllable, exercise-mimetic approach with a defined mechanism. Our study identified osteocyte senescence as a therapeutically tractable pathological node in SOP and uncovered a mechanism by which mechanical stimulation suppressed osteocyte senescence through mitophagy-mediated mitochondrial quality control. Mechanical stimulations derived from exercise in vivo and oscillating fluid flow (OFF) in vitro activated PGC-1α–dependent mitophagy, alleviated mitochondrial oxidative damage, limited mitochondrial DNA leakage, and dampened the senescence-associated secretory phenotype (SASP). Conversely, pharmacological inhibition of mitophagy or genetic silencing of PGC-1α abrogated the anti-senescent and mitochondria-protective effects of mechanical stimulation. Guided by this mechanism, we engineered a bone-targeted superparamagnetic iron oxide nanoparticle platform (SPIONs-DSS 6 ) and showed that, under an external variable magnetic field (VMF), SPIONs-DSS 6 mimicked exercise-derived mechanical stimulation, activated PGC-1α–dependent mitophagy, suppressed osteocyte senescence, and mitigated SOP progression while exhibiting favorable biosafety. Collectively, our findings established a mechanistic framework in which mechanical stimulation restrains osteocyte senescence via a PGC-1α–dependent mitophagy axis and supported bone-targeted magnetic mechanical stimulation as a translational exercise-mimetic strategy for SOP.