In vivo generation of fibrolytic macrophages via LNP-CSF1 mRNA attenuates liver fibrosis.

Liver fibrosis, a common consequence of chronic liver injury, imposes a substantial global health burden. While autologous infusion of ex vivo-induced macrophages has shown therapeutic potential, such cell-based strategies remain limited by high costs and operational complexity, underscoring the necessity for non-cellular alternatives. Here, we aim to directly generate therapeutic macrophages with fibrolytic capacity within the liver. We observed elevated levels of macrophage colony-stimulating factor 1 (CSF1) during the resolution of liver regeneration-induced fibrosis. Given the well-established role of CSF1 in recruiting and activating monocyte-macrophages, as well as its use as a key cytokine for the ex vivo induction of therapeutic macrophages, we delivered CSF1-mRNA via lipid nanoparticles (LNPs) to enhance its local expression in the liver. This approach effectively recruited macrophages and promoted their differentiation into a fibrolytic phenotype. The in vivo-generated macrophages exhibited increased collagenase expression and enhanced phagocytic activity. Moreover, their transcriptomic and functional profiles closely resembled those of ex vivo-induced therapeutic macrophages. This approach significantly alleviated fibrosis in multiple mouse models. Together, this work provides preclinical proof of concept that LNP-CSF1-based in situ cellular therapy represents a promising non-cellular strategy for combating liver fibrosis.