Hepatic stellate cell-targeted chemo-gene therapy for liver fibrosis using fluorinated peptide-lipid hybrid...

Exploring precise and effective treatments for liver fibrosis is urgent. The effective therapy for liver fibrosis depends on the specific delivery of antifibrotic drugs to activated hepatic stellate cells (aHSCs). However, this is a challenging task due to pathological barriers, primarily caused by collagen deposition. This study developed vitamin A-functionalized fluorinated peptide/lipid hybrid nanoparticles to co-deliver sorafenib and siRNA against HSP47 (SF-siHSP47@VFPL NPs). This nanoparticle formulation offers significant advantages due to its fluorine‑fluorine and electrostatic interactions, allowing for high SF and siHSP47 loading efficiency and sustained drug release. Importantly, in vitro cell uptake and in vivo biodistribution revealed that VA functionalization significantly improved aHSC-targeted delivery efficiency by engaging retinol-binding protein receptors on HSCs. Furthermore, it dramatically reduced extracellular matrix deposition, as evidenced by diminished levels of liver fibrosis-associated genes (HSP47, TIMP-1, and collagen I), promoting collagen breakdown and preventing collagen production, thus overcoming drug delivery barriers. Thus, SF-siHSP47@VFPL NPs demonstrated optimal antifibrotic effects by triggering apoptosis and ferroptosis in aHSCs. In liver fibrosis mouse models, SF-siHSP47@VFPL NPs remodeled the pathological environment and restored liver functionality through a marked reduction in serum liver transferases, hydroxyproline content, collagen deposition, and α-SMA and CD31 expression in liver tissue, resulting in alleviated liver fibrosis. Consequently, SF-siHSP47@VFPL NPs showed significant potential for HSC-targeted, chemo-gene therapy in the treatment of liver fibrosis.