Macrophage microRNA-146a is a central regulator of the foreign body response to biomaterial implants.

Host recognition and immune-mediated foreign body response (FBR) to biomaterials can adversely affect the functionality of implanted materials. FBR presents a complex bioengineering and medical challenge due to the lack of current treatments, making the detailed exploration of its molecular mechanisms crucial for developing new and effective therapies. To identify key molecular targets underlying the generation of FBR, here we perform analysis of microRNAs (miR) and mRNAs responses to implanted biomaterials. We found that (a) miR-146a levels inversely affect macrophage accumulation, foreign body giant cell (FBGC) formation, and fibrosis in a murine implant model; (b) macrophage-derived miR-146a is a crucial regulator of the FBR and FBGC formation, as confirmed by global and cell-specific knockout of miR-146a; (c) miR-146a modulates genes related to inflammation, fibrosis, and mechanosensing; (d) miR-146a modulates tissue stiffness near the implant during FBR as assessed by atomic force microscopy; and (e) miR-146a is linked to F-actin production and cellular traction force induction as determined by traction force microscopy, which are vital for FBGC formation. These novel findings suggest that targeting macrophage miR-146a could be a selective strategy to inhibit FBR, potentially improving the biocompatibility of biomaterials.