Nanoparticle-mediated liver targeted delivery of IFN-γ confers enhanced anti-fibrotic efficacy with reduced systemic toxicity.

IFN-γ has been shown to exert potent anti-fibrotic effects in early stages of liver fibrosis, but the drug development has been impeded by systemic toxicity arising from off-target receptor activation. To overcome this therapeutic challenge, a nanodelivery platform (~200 nm) through covalent conjugation of sulfated hyaluronan (S-HA) with branched polyethyleneimine (PEI) was developed. Upon loading with IFN-γ, the nanoplatform achieved significantly enhanced hepatic accumulation effect. The resulting S-HA-PEI-IFN-γ formulation significantly attenuated M1 type macrophage polarization and associated pro-inflammatory cytokine release induced by free IFN-γ treatment, the key contributors to systemic adverse effects. Mechanistically, the nanoparticle of S-HA-PEI within the formulation exhibited synergistic effect with IFN-γ to suppress hepatic stellate cell (HSC) activation by blocking TGF-β/Smads signaling pathway. In a CCl4-induced murine liver fibrosis model, S-HA-PEI-IFN-γ administration achieved remarkable reduction in collagen deposition as compared to free IFN-γ treatment, accompanied by concurrent downregulation of Collagen-I (ColI) and α-smooth muscle actin (α-SMA) expression. By integrating targeted delivery, toxicity mitigation and synergistic anti-fibrotic effect, the S-HA-PEI-IFN-γ nano-therapeutic represents a promising transformative strategy for combating liver fibrosis.