In Situ Biomineralization Enhances Mitochondrial Transplantation to Differentiating Osteoclast Precursors for Suppressing Cancer-Induced Osteolysis.

Cancer-induced bone osteolysis is a common complication of multiple malignancies and may actively contribute to bone metastasis. Its core pathology is closely associated with mitochondrial metabolic dysfunction during osteoclast differentiation. In this study, a mitochondrial transplantation strategy based on in situ biomineralization (Mito@ZIF@RGD) was developed to overcome multiple delivery barriers in differentiating osteoclast precursor cells. A zeolitic imidazolate framework-8 (ZIF-8) shell was formed via the in situ self-assembly of Zn2+ and 2-methylimidazole on the mitochondrial membrane, thereby enhancing mitochondrial stability. Meanwhile, cyclic RGD (arginine-glycine-aspartic acid) peptides were coordinated with exposed Zn2+ sites on the outer shell to promote αvβ3-mediated uptake during osteoclast differentiation. Furthermore, the sustained Zn2+ release from the ZIF-8 biomineralization reshaped intracellular ionic homeostasis, thereby improving the durability of therapeutic efficacy following mitochondrial transplantation. In vitro experiments demonstrated that ZIF-8 encapsulation stabilized mitochondria and enabled sustained adenosine triphosphate production for more than 48 h. RGD modification improved cellular uptake efficiency by approximately 55% in differentiating osteoclast precursors, while the mildly acidic microenvironment triggered the coordinated release of mitochondria and Zn2+, effectively reducing intracellular reactive oxygen species levels and osteoclast formation. In vivo, Mito@ZIF@RGD treatment promoted the recovery of bone mineral density, suppressed osteoclast surface area formation by approximately 30%, and preserved bone microstructural integrity. Therefore, as a stable, specific, and durable mitochondrial transplantation platform modulating cellular metabolism during osteoclast differentiation, Mito@ZIF@RGD represents a stable and promising platform for the treatment of cancer-induced osteolysis and other metabolic imbalance-associated bone diseases.