Following an injury at the implantation position, blood-material interactions form a fibrin architecture, which serves as the initial activator of foreign body response (FBR). However, there is limited knowledge regarding how the topography of fibrin architectures regulates macrophage behavior in mitigating FBR. Mechanical cues of the microenvironment have been reported to shape immune cell functions. Here, we investigated macrophage mechanobiology at the organelle level by constructing heterogeneous fibrin networks. Based on findings , we demonstrated that adhesion-mediated differentiation of mitochondrial function modulated macrophage polarization. The finite activation of integrin signaling upregulated transglutaminase 2 (Tgm2) in a trans-manner, augments PGC1α-mediated mitochondrial biogenesis. Our study highlighted the previously overlooked spatial structures of host proteins adsorbed on material surfaces, advocating for a paradigm shift in material design strategies, from focusing solely on physical properties to considering the modification of host proteins.