A Nanococktail Strategy Regulating Circadian Clock and Re-Establishing Bone-Immune Balance for the Treatment of Senile Osteoporosis

Feb 18, 2026ACS nano

A Nanoparticle Approach to Adjust the Body Clock and Restore Bone-Immune Balance for Treating Age-Related Bone Loss

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

A significant proportion of melatonin-loaded nanovesicles are phagocytosed by bone marrow-derived macrophages, restoring their circadian rhythm gene expression.

Circadian rhythm disorders may impair the efferocytosis function of macrophages, leading to compensatory actions by bone mesenchymal stem cells.
BMSCs may experience reduced osteoblastic differentiation, which is associated with the development of senile osteoporosis.
Targeting RANKL within the bone microenvironment using bone-targeting nanovesicles could inhibit osteoclast formation.
The use of specific nanococktails may promote osteogenesis by activating signaling pathways in osteoblasts.
Restoration of macrophage efferocytosis function may relieve BMSCs from compensatory actions, enhancing their ability to support bone formation.

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Circadian rhythm disorders impair the efferocytosis function of macrophages, leading to compensatory nonprofessional efferocytosis by bone mesenchymal stem cells (BMSCs). However, this BMSC-mediated efferocytosis may reduce their osteoblastic differentiation, contributing to bone loss. Consequently, circadian rhythm disorders and abnormal efferocytosis by BMSCs are considered crucial factors in the pathogenesis of senile osteoporosis (SOP). Currently, most pharmaceutical treatments for SOP focus on re-establishing the osteoblast/osteoclast balance, often overlooking the importance of restoring the circadian clock and the efferocytosis function of macrophages. In this study, we developed a nanococktail strategy utilizing melatonin-loaded bone-targeting nanovesicles (NVs) prepared from gene-edited BMSC membranes. Due to the overexpression of receptor activator of nuclear factor-κB (RANK) and C-X-C motif chemokine receptor 4 (CXCR4), these NVs can specifically target and clear the RANK ligand (RANKL) within the bone microenvironment, thereby inhibiting osteoclastogenesis. Following the (AspSerSer)modification of partial NVs, these NVs are redistributed to bone formation surfaces, where they activate RANKL reverse signaling in osteoblasts, thereby promoting osteogenesis. Importantly, a significant proportion of these NVs are phagocytosed by bone marrow-derived macrophages, which subsequently restore their expression of essential circadian rhythm genes and efferocytosis function. Consequently, BMSCs are relieved from nonprofessional efferocytosis, leading to the restoration of their osteogenic capacity. In summary, this study introduces an innovative nanococktail strategy for the treatment of SOP by modulating both circadian clock-dependent efferocytosis function and the osteoblast/osteoclast balance. 6

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A Nanococktail Strategy Regulating Circadian Clock and Re-Establishing Bone-Immune Balance for the Treatment of Senile Osteoporosis

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