Ni‐MOF Engineered System Targeting Macrophage Aurora A Kinase for Bone Loss Prevention Through PD‐L1 Activation

Abstract Postmenopausal bone loss due to estrogen deficiency necessitates effective therapeutic strategies. Our study explores targeting macrophage Aurora A kinase to mitigate bone loss. Aurora A kinase phosphorylation is observed being increased in bone marrow‐derived macrophages (BMDMs) from ovariectomy (OVX) mice, along with a reduction in programmed death‐ligand 1 (PD‐L1) expression. Detailed analysis reveals that PD‐L1 plays an immunomodulatory role by lowering the ratio of T helper 17 cells and regulatory T cells. The metabolic shift toward glycolysis through transcriptome sequencing, induced by Aurora A kinase inhibition, is essential for PD‐L1 expression in BMDMs. The interaction between Aurora A kinase and cytochrome C oxidase subunit 5B is found to enhance PD‐L1 expression. To apply these findings therapeutically, a multifunctional system is developed using a Nickel‐metal organic framework combined with bisphosphonate and MLN8237 (BP@Ni‐MOF/MLN8237). This system targets bone tissues through bisphosphonate and effectively delivers MLN8237 to macrophages, promoting PD‐L1 expression for a favorable immune environment. Moreover, this system exhibits an obvious angiogenic effect. The present study highlights the crucial roles of macrophage Aurora A kinase and PD‐L1 in maintaining bone homeostasis as well as the angiogenesis effect by Ni‐MOF engineered system, presenting a promising therapeutic approach to prevent postmenopausal bone loss.