Dual-Targeted Nanoplatform Regulating the Bone Immune Microenvironment Enhances Fracture Healing

Abstract

The immune system and skeletal system are closely linked. Macrophages are one of the most important immune cells for bone remodeling, playing a prohealing role mainly through M2 phenotype polarization. Baicalein (5,6,7-trihydroxyflavone, BCL) has been well documented to have a noticeable promotion effect on M2 macrophage polarization. However, due to the limitations in targeted delivery to macrophages and the toxic effect on other organs, BCL has rarely been used in the treatment of bone fractures. In this study, we developed mesoporous silica and Fe3O4 composite-targeted nanoparticles loaded with BCL (BCL@MMSNPs-SS-CD-NW), which could be magnetically delivered to the fracture site. This induced macrophage recruitment in a targeted manner, polarizing them toward the M2 phenotype, which was demonstrated to induce mesenchymal stem cells (MSCs) toward osteoblastic differentiation. The mesoporous silicon nanoparticles (MSNs) were prepared with surface sulfhydrylation and amination modification, and the mesoporous channels were blocked with β-cyclodextrin. The outer layer of the mesoporous silicon was added with an amantane-modified NW-targeting peptide to obtain the targeted nanosystem. After entering macrophages, BCL could be released from nanoparticles since the disulfide linker could be cleaved by intracellular glutathione (GSH), resulting in the removal of cyclodextrin (CD) gatekeeper, which is a key element in the pro-bone-remodeling functions such as anti-inflammation and induction of M2 macrophage polarization to facilitate osteogenic differentiation. This nanosystem passively accumulated in the fracture site, promoting osteogenic differentiation activities, highlighting a potent therapeutic benefit with high biosafety.

Metformin Facilitates Osteoblastic Differentiation and M2 Macrophage Polarization by PI3K/AKT/mTOR Pathway in Human Umbilical Cord Mesenchymal Stem Cells

“…It is widely believed that different macrophage polarization states contribute to different conditions of bone metabolism [ 3 , 21 , 22 ]. Zhou et al demonstrated that induction of M2 polarization facilitated osteogenic differentiation [ 21 ].…”

“…It is widely believed that different macrophage polarization states contribute to different conditions of bone metabolism [ 3 , 21 , 22 ]. Zhou et al demonstrated that induction of M2 polarization facilitated osteogenic differentiation [ 21 ]. Kang et al demonstrated that the M2 macrophage extracellular vesicles increased osteoinductive gene expression of MSCs [ 41 ].…”

“…On the one hand, factors such as metformin could polarize the macrophages and inhibit the inflammasome activation [ 20 ]. On the other hand, these polarized macrophages could in turn modulate bone milieu and remodeling [ 21 – 23 ]. Therefore, a better understanding of the cross-talk between macrophages and MSCs can revolutionize our understanding of bone homeostasis.…”

IL-6 and Leptin Are Potential Biomarkers for Osteoporotic Fracture Risk Assessment and Prediction of Postmenopausal Women with Low Bone Mass: A Follow-Up Study Using a Regional Sample Cohort

“…Inflammatory microenvironment mediated by the immune system in vivo is considered to be a major reason of abnormal bone metabolism. It may lead to osteoclast activation to accelerate bone loss [27,28], increase the risk of fracture [29,30], and slow down the healing rate of fracture [31,32]. Many medicines are used to treat osteoporosis and repair the bone tissue by alleviating the expression of tissue inflammatory factors [33][34][35].…”

Enhanced Immunotherapy Based on Combining the Pro-phagocytosis and Anti-phagocytosis Checkpoint Blockade for Tumor Eradication

“…The synthesis of MSN–SS–alkyne is referred to in our previous work. ,, 100 mg of MSN–SS–alkyne was dispersed in a mixed solution of 5 mL of methanol and 5 mL of PBS. 25 mg of DOX hydrochloride or 25 mg of RRx-001 was added, and the reaction mixture was vigorously stirred at room temperature for 24 h. Then, 100 mg of mono-6-azido-β-CD, 100 mg of CuSO 4 ·5H 2 O, and 170 mg of sodium ascorbate were added.…”