Pollen-like mesoporous silica nanoparticles facilitate macrophage-mediated anti-inflammatory response via physical contact cues in the osteoimmune microenvironment

Nanomaterial-mediated macrophage immune response plays a crucial role in bone regeneration microenvironment. Mesoporous silica nanoparticles are widely used as nano-drug carriers, imaging agents, and bioactivity regulators for potential tissue regeneration. It is known that surface topography features of nanomaterials play an important regulatory role in the immune response. In this study, it was found that the pollen-like surface morphology of mesoporous silica nanoparticles (PMSNs) inhibited the expression of pro-inflammatory markers at gene and protein levels in macrophages (RAW 264.7 cells) compared to the smooth surface morphology of mesoporous silica nanoparticles (MSNs). Scanning electron microscopy images showed distinct macrophage membrane surface binding patterns of MSNs and PMSNs. MSNs were more evenly dispersed across the macrophage cell membrane, while PMSNs were aggregated on the membrane and prevented the M1 polarization of macrophages. PMSNs-induced macrophage anti-inflammatory responses were associated with up-regulation of the cell surface receptor CD28 and inhibition of ERK phosphorylation. TEM images showed that macrophages phagocytosed both MSNs and PMSNs while inhibiting nanoparticle phagocytosis did not affect the expression of anti-inflammatory genes and proteins. Moreover, PMSNs-induced conditioned medium from macrophages promoted osteogenic differentiation of mouse bone marrow-derived stromal cells (mBMSCs), evidenced by increased mineralization and osteogenic marker BMP2 expression via Alizarin Red S and LSCM assays compared to MSNs-induced conditioned medium. Moreover, a lipopolysaccharide (LPS)-induced osteolysis model in mouse cranial bone further demonstrated that PMSNs prevent bone resorption by mitigating LPS-induced inflammation. Our results revealed that PMSNs-mediated macrophage immunomodulation promotes bone regeneration via surface topology-related physical contact cues. STATEMENT OF SIGNIFICANCE: Nanomaterials have been widely used in bone regeneration. The immune response of macrophages induced by nanomaterials, plays a crucial role in bone regeneration. However, most nanomaterial immunomodulatory research focus on macrophage internalization or phagocytosis. The early contact between the cell membrane and nanomaterials is often easily overlooked. To clarify how early contact between nanomaterial-cell membrane regulates macrophage immune response. We developed MSN particles with special pollen-like surface morphology and studied the impact of nanoparticle morphology on the early contact between materials and macrophage cell membranes, as well as the subsequent impact on macrophage immune response and bone regeneration and related regulatory mechanisms. The results can provide new guidance for the design and development of osteoimmunomodulatory nanomaterials.