Silica nanocarrier-mediated intracellular delivery of rapamycin promotes autophagy-mediated M2 macrophage polarization to regulate bone regeneration

Qing Zhang; Mengyu Xin; Shuang Yang; Qiuyu Wu; Xi Xiang; Tianqi Wang; Wen Zhong; Marco N Helder; Richard T Jaspers; Janak Lal Pathak; Yin Xiao

doi:10.1016/j.mtbio.2023.100623

Silica nanocarrier-mediated intracellular delivery of rapamycin promotes autophagy-mediated M2 macrophage polarization to regulate bone regeneration

Mater Today Bio. 2023 Mar 31:20:100623. doi: 10.1016/j.mtbio.2023.100623. eCollection 2023 Jun.

Authors

Qing Zhang^{1

2}, Mengyu Xin¹, Shuang Yang¹, Qiuyu Wu¹, Xi Xiang¹, Tianqi Wang¹, Wen Zhong¹, Marco N Helder³, Richard T Jaspers^{1

2}, Janak Lal Pathak¹, Yin Xiao^{1

4

5}

Affiliations

¹ Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou 510182, China.
² Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, 1081 BT Amsterdam, the Netherlands.
³ Department of Oral and Maxillofacial Surgery/Oral Pathology, Amsterdam University Medical Centers and Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, 1081 HV Amsterdam, the Netherlands.
⁴ School of Medicine and Dentistry & Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4222, Australia.
⁵ The Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM), Queensland University of Technology, Brisbane, QLD 4000, Australia.

Abstract

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.

Keywords: Autophagy; Hollow silica nanoparticles; Macrophages; Osteogenesis; Rapamycin.