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

作者：Yu Zhang, Changpeng Liu, Pengzhen Zhuang, Chengcheng Li, Huan Zhang, Yuanyuan Liu, Yu Chen, Yang Wu, Longxi Wu, Yawei Du, Wenguo Cui, Hongbo Zhang · 发表于：Research · 年份：2026 · DOI：10.34133/research.1410 · 研究领域：Bone health and treatments、Bone Metabolism and Diseases、Alkaline Phosphatase Research Studies

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 Zn 2+ and 2-methylimidazole on the mitochondrial membrane, thereby enhancing mitochondrial stability. Meanwhile, cyclic RGD (arginine–glycine–aspartic acid) peptides were coordinated with exposed Zn 2+ sites on the outer shell to promote αvβ3-mediated uptake during osteoclast differentiation. Furthermore, the sustained Zn 2+ 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 Zn 2+ , effectively reducing intracellular reactive oxygen species levels and...