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.