Rescuing Mitochondrial Dysfunction in Macrophages Prevents Osteonecrosis of the Jaw in Anti‐Resorptive Therapy

Abstract Mitochondria‐driven macrophage dysregulation contributes significantly to inflammatory disease progression; however, the mechanism underlying bisphosphonate‐related osteonecrosis of the jaw (BRONJ) remains unclear. This study demonstrates that zoledronic acid (ZA) disrupts mitochondrial bioenergetic function in macrophages, leading to elevated mitochondrial membrane potential, excessive mitochondrial reactive oxygen species (mtROS), and increased HIF‐1α expression, which together promote a pro‐inflammatory transition in macrophages. ZA further inhibits autophagy by activating the TLR4‐MyD88/PI3K‐AKT‐mTOR pathway, preventing the clearance of dysfunctional mitochondria and sustaining superoxide production. Genetic loss of Atg5 in innate immune cells disrupts autophagosome maturation and markedly worsens ZA‐induced BRONJ development. To restore mitochondrial degradation and biofunction, ZA‐loaded nanoparticles incorporating the mTOR inhibitor rapamycin (ZDPR) are developed. ZDPR effectively prevents BRONJ and exerts therapeutic benefits in osteoporosis and osteolysis. These findings highlight bone‐targeted mitochondria rescue as a promising strategy to enhance antiresorptive therapy.