Coassembled peptide nanoparticles enable stage-specific diagnosis and targeted therapy of hepatic fibrosis by inhibiting macrophage-driven inflammation.

Abstract

Hepatic fibrosis represents a major unmet clinical challenge, given its insidious progression and the lack of effective diagnostic and therapeutic strategies. To address this gap, we constructed supramolecular assemblies integrating an antifibrotic peptide with indocyanine green (ICG), a clinically approved dye for hepatic function assessment. The resulting ICG-peptide nanoparticles (ICG-peptide-NPs) integrate the therapeutic activity of the antifibrotic peptide with the diagnostic capacity of ICG. They significantly extend the diagnostic window of ICG from 15 to 60 min and improve diagnostic performance for liver fibrosis staging. Benefiting from prolonged blood circulation and selective accumulation in fibrotic liver tissue, ICG-peptide-NPs exhibit markedly enhanced antifibrotic efficacy. Mechanistically, they inhibit macrophage M1 polarization through the FPR2/STAT3 pathway. This effect reduces inflammatory factor secretion, suppresses extracellular matrix deposition, and normalizes serum liver function markers. We further demonstrate that ICG-peptide-NPs dampen aberrant immune responses during liver fibrosis progression by blocking the recruitment of monocyte-derived macrophages. The FPR2/STAT3-mediated signaling pathway is further validated at the transcriptomic level via whole-genome RNA sequencing. With favorable biocompatibility and enhanced antifibrotic efficacy, these multifunctional peptide assemblies offer a novel strategy for the integrated diagnosis and treatment of hepatic fibrosis.