Supramolecular Self-Assembly of Lycorine with Glycyrrhizic Acid into a Nanodrug for Safe and Sustained Anti-HBV Therapy.

Achieving a functional cure for chronic hepatitis B remains a major challenge, as conventional therapies struggle to eliminate the hepatitis B surface antigen (HBsAg) and subsequently restore adaptive antiviral immunity. Lycorine (LY), a compound with broad-spectrum antiviral activity, has shown particular promise inhibiting HBsAg secretion. However, its clinical application is severely limited by significant cytotoxicity, the induction of apoptosis, a short half-life, and adverse in vivo effects. To overcome these barriers and enhance its therapeutic potential, we designed a self-assembled nanomedicine (LGN) by co-assembling LY with glycyrrhizic acid, a natural anti-HBV agent. This strategy not only protected LY from premature degradation and enabled its sustained release in the colon but also markedly attenuated LY-induced systemic toxicity. Notably, LGN effectively suppressed HBsAg secretion (IC50 = 2.15 ± 0.09 μM) with a selectivity index (SI > 93) over two-fold higher than that of LY alone (SI = 39.26). Furthermore, LGN concurrently inhibited HBV DNA replication, pgRNA transcription, and the expression of viral protein HBc and HBx, indicating a multitargeted, host-dependent mechanism distinct from nucleos(t)ide analogs. Treatment with this nanomedicine in the HDI model further demonstrated its therapeutic potential against HBV with apparent safety. Further transcriptomic study confirmed that LGN induces a distinct host transcriptional program that disrupts multiple critical stages of the HBV life cycle including viral entry, covalently closed circular DNA maintenance, gene transcription, and immune evasion. Collectively, these findings provide valuable insights into exploiting natural products like LY for antiviral therapy and underscore the potential of self-assembly technology in improving drug safety and pharmacokinetic profiles.