Biomimetic nanoparticles camouflaged with M2 macrophage membrane for osteoporosis therapy: A triple-action strategy that upregulates anti-inflammation and osteogenic responses while suppressing MMP-9

Osteoporosis is a systemic skeletal disorder characterized by bone loss and microstructural deterioration, and its pathogenesis is closely associated with dysregulation of the bone marrow immune microenvironment. In this study, bioinformatic analysis first revealed significant oxidative stress and mitochondrial metabolic dysfunction in macrophages within the osteoporotic microenvironment. Based on this, we constructed a biomimetic nanoplatform (ZCM2) composed of ZIF-8@CaCO3 core-shell nanoparticles camouflaged with M2 macrophage membranes, designed to achieve comprehensive osteoporosis therapy through a triple synergistic mechanism: the ZIF-8 core scavenges reactive oxygen species to exert antioxidant and anti-inflammatory effects, inhibits MMP-9 secretion to reduce pathological bone resorption, and the CaCO3 shell releases calcium ions to promote osteogenic differentiation. ZCM2 exhibited favorable biosafety, high cellular uptake efficiency, and excellent bone-targeting capability. Mechanistic studies demonstrated that ZCM2 upregulates the expression of Nrf2 and HO-1, downregulates the expression of NF-κB p65, and significantly reduces the secretion of matrix metalloproteinase-9 (MMP-9) by macrophages, thereby attenuating bone resorption. Meanwhile, calcium ions released from the CaCO3 shell activate the RUNX2/OSX/OPN signaling axis, promoting osteogenic differentiation of bone marrow mesenchymal stem cells. In an ovariectomized mouse model of osteoporosis, ZCM2 markedly improved bone microarchitecture, promoted new bone formation, and effectively inhibited bone resorption activity. Collectively, this biomimetic nanoplatform integrates anti-inflammatory, anti-resorptive, and pro-osteogenic functions, offering a multifaceted synergistic therapeutic strategy for osteoporosis.