| Summary: | Targeting macrophages to regulate the immune microenvironment is a new strategy for bone regeneration with nano-drugs. Nano-drugs have achieved surprising anti-inflammatory and bone-regenerative effects, however, their underlying mechanisms in macrophages remain to be clarified. Macrophage polarization, immunomodulation, and osteogenesis are governed by autophagy. Rapamycin, an autophagy inducer, has shown promising results in bone regeneration, but high dose-mediated cytotoxicity and low bioavailability hinder its clinical application. This study aimed to develop rapamycin-loaded virus-like hollow silica nanoparticles (R@HSNs) which are easily phagocytosed by macrophages and translocated to lysosomes. R@HSNs induced macrophage autophagy, promoted M2 polarization, and alleviated the degree of M1 polarization as indicated by the downregulation of inflammatory factors IL-6, IL-1β, TNF-α, and iNOS, and upregulation of anti-inflammatory factors CD163, CD206, IL-1ra, IL-10, and TGF-β. These effects were nullified by cytochalasin B-induced inhibition of R@HSNs uptake in macrophages. The conditioned medium (CM) collected from R@HSNs-treated macrophages promoted osteogenic differentiation of mouse bone marrow mesenchymal stromal cells (mBMSCs). In a mouse calvaria defect model, free rapamycin treatment was inhibited, but R@HSNs robustly promoted bone defect healing. In conclusion, silica nanocarrier-mediated intracellular rapamycin delivery to macrophages effectively triggers autophagy-mediated M2 macrophage polarization, further enhancing bone regeneration by triggering osteogenic differentiation of mBMSCs.
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