Ultrasound-Triggered HSC Membrane-Cloaked Nanotherapeutics Attenuate Liver Fibrosis via Simultaneous Modulation of Mitophagic Flux and the TGF-β/Smad3 Cascade

Abstract This study presents an ultrasound-triggered therapeutic platform based on melatonin-loaded and perfluoropentane-encapsulated mesoporous silica nanoparticles, which are further cloaked with activated hepatic stellate cell membranes (HM-Mel@PFP-MSNs), designed for the precision treatment of liver fibrosis. This innovative drug delivery system leverages the inherent targeting properties of cell membrane coatings, effectively functioning as a “gatekeeper” that prevents premature drug release. By incorporating melatonin and perfluoropentane (PFP), our approach enables ultrasound-mediated controlled release, enhancing therapeutic efficacy. In vitro investigations revealed that upon ultrasound activation, HM-Mel@PFP-MSNs significantly inhibited the activation of hepatic stellate cells (HSCs) and alleviated mitochondrial damage. Mechanistic studies employing Western blot analysis revealed that this nanotherapeutic strategy was associated with altered expression of autophagy-related proteins, including a reduced LC3-II/I ratio, increased P62 accumulation, and downregulated PINK1/Parkin. These findings suggest an overall suppression of autophagic activity, encompassing both general autophagy and mitophagy; however, a causal link remains to be established. Furthermore, using a rat model of liver fibrosis, robust histological assessments (including HE, Masson, Sirius Red, and α-SMA staining) demonstrated that our system markedly ameliorated fibrotic lesions under precise ultrasound guidance. This research introduces a novel strategy that integrates targeted delivery, controlled drug release, and visualizable therapeutic outcomes, thereby representing a significant advancement in the management of liver diseases. By simultaneously modulating mitophagic flux and the TGF-β/Smad3 signaling cascade, our HM-Mel@PFP-MSN-based nanotherapeutics open new avenues for liver fibrosis treatment, emphasizing the potential of leveraging ultrasound in enhancing therapeutic precision and efficacy.