Silk films with distinct surface topography modulate plasma membrane curvature to polarize macrophages

The physical properties of a biomaterial play a vital role in modulating macrophage polarization. However, discerning the specific effects of individual parameters can be intricate due to their interdependencies, limiting the mechanism underlying a specific parameter on the polarization of macrophages. Here, we engineered silk fibroin (SF) films with tunable surface roughness while maintaining similar physical properties by combining casting and salting out techniques. We demonstrate that increased surface roughness in SF films promotes M2-like macrophage polarization, characterized by enhanced secretion of anti-inflammatory cytokines. Transcriptomic analysis unveils the modulation of genes associated with extracellular matrix-cell interactions, highlighting the role of surface topography in regulating cellular processes. Mechanistically, we show that surface roughness induces macrophage membrane curvature, facilitating integrin αv endocytosis and thereby inhibiting the integrin-NF-kB signaling pathway. In vivo implantation assays corroborate that rough SF films substantially mitigate early inflammatory responses. This work establishes a direct link between surface roughness and intracellular signaling in macrophages, adding to our understanding of the biomaterial surface effect at the material-cell interface and bringing insights into material design.