Abstract

Epigallocatechin gallate (EGCG) has shown antiviral potential against the hepatitis B virus (HBV) by restoring lysosomal acidification; however, its application is limited by poor stability and low intestinal permeability. Here, a dual-shell chitosan/ferritin nanosystem (CHE) was developed to enhance the EGCG delivery and functionality. CHE achieved an encapsulation efficiency of 13.61% with a uniform nanoscale size distribution. Compared with free EGCG and single-shell HE, CHE improved storage stability and delayed EGCG release under simulated gastrointestinal conditions. In a Caco-2/HepG2.2.15 or HepAD38 coculture model, CHE enhanced transepithelial transport and intracellular delivery while maintaining epithelial barrier integrity. Mechanistically, CHE promoted lysosomal acidification, increased cathepsin B maturation, and restored autophagic flux, accompanied by reductions in HBV DNA, pgRNA, HBsAg, and HBeAg levels. These findings demonstrate that a dual-shell nanocage integrates stability enhancement with functional intracellular modulation, providing a promising strategy to improve the antiviral efficacy of polyphenols.