Mechanically Priming Macrophages for Liver fibrosis (PriMaL)

Objective

Chronic liver diseases cause about 2 million deaths annually, with fibrosis—driven by excess extracellular matrix from activated stellate cells—being the main risk factor for hepatocellular carcinoma, yet effective therapies remain scarce and limited by side effects. Immune-based cell therapies, particularly macrophages, hold promise for liver repair, but clinical benefits have been restricted, likely due to insufficient priming into a stable antifibrotic state. This fellowship aims to address this need by developing a novel therapy based on priming macrophages through mechanical stimulation, harnessing cell “mechanical memory”—a persistent cellular genetic state that remain even after the mechanical stimulus is removed— as safer, more scalable, and cost-effective alternative to genetic engineering. The project introduces the engineering of a light-responsive hydrogel based on bacterial nanocellulose (BNC), a highly biocompatible natural polymer, functionalized with azobenzene molecules to enable on-demand, in-situ tuning of stiffness. This system allows to deliver precise spatiotemporal controlled mechanical cues to the embedded macrophages with the aim to guide their phenotype toward an anti-inflammatory state, thus offering a promising strategy to restore liver functions.