Vitamin A-Modified Berberine Liposomes Potentiate Anti-Fibrotic Effects Through Enhanced Hepatic Stellate Cell Uptake.

BACKGROUND: Activated hepatic stellate cells (HSCs) are key drivers of liver fibrosis, which progresses irreversibly without effective intervention. The natural alkaloid berberine (BBR) has been reported to possess anti-fibrotic activity. However, the poor solubility and injection-associated systemic toxicity of free BBR confine it to oral administration, resulting in its low bioavailability. Nanocarrier encapsulation addresses these drawbacks, and we therefore aimed to develop an HSC‑preferential delivery system with loaded BBR to improve its anti-fibrosis effects without causing systemic toxicity. METHODS: In this study, vitamin A-modified lipids were synthesized to fabricate HSC‑preferential liposomes to encapsulate BBR and enhance delivery efficiency. This targeted BBR liposomal system was physiochemically characterized, followed by in vitro assessments of cellular uptake and inhibition of HSCs activation. In vivo animal studies were performed to validate the therapeutic efficacy of targeted BBR liposomes against hepatic fibrosis. RESULTS: VA-modified BBR liposomes had an average size of 165.9 ± 7.1 nm with the desired size distribution. Compared to untargeted BBR liposomes, VA-modified liposomal BBR showed significantly increased HSC uptake, thus indicating enhanced inhibition of HSC activation by dramatically reducing HSC migration and proliferation abilities and decreased collagen1 expression in vitro. Intriguingly, contrary to earlier literature, we detected elevated α‑SMA expression upon BBR treatment despite the suppression of cell migration, proliferation and collagen production. In hepatic fibrosis mouse models, targeted BBR liposomes at 5 mg/kg significantly decreased aspartate aminotransferase and alanine aminotransferase levels in serum, and markedly reduced fibrotic areas and collagen synthesis and deposition, while equal doses of untargeted BBR liposomes showed negligible effects. CONCLUSION: Our results demonstrate that VA-functionalized liposomes facilitate the efficient targeted delivery of BBR to activated HSCs in hepatic fibrosis. Such targeted delivery augments the inherent anti-fibrotic potency of free BBR, highlighting the potential of this nanoplatform for hepatic fibrosis treatment.