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.