Integrated in silico design of self-assembled herbal bioactives–polysaccharides nanoformulation for targeted therapy against gastric pathogen Helicobacter pylori

Bioactive polysaccharides and herbal compounds exhibit intrinsic antibacterial activity against the gastric pathogen Helicobacter pylori, but their therapeutic efficacy is limited by poor oral bioavailability, nonspecific distribution, and instability during self-assembly. Here, we integrated molecular dynamics and density functional theory (DFT) simulations with experimental validation to rationally design a self-assembled nanocarrier for targeted H. pylori therapy. Increasing the proportion of positively charged chitosan enhanced co-assembly with negatively charged fucoidan, and an optimized 5:1 ratio (C5F1) produced uniform, well-dispersed nanoparticles. Among screened herbal compounds, arctigenin (ARG) showed the strongest affinity for C5F1, driven by hydrogen bonding and van der Waals interactions. DFT analysis revealed a larger HOMO-LUMO gap for chitosan-ARG than for fucoidan-ARG, indicating more active adsorption sites and a lower energy barrier. The resulting ARG@C5F1 nanocomposite exhibited pH-responsive drug release mediated by chitosan protonation and electrostatic modulation. ARG@C5F1 demonstrated enhanced gastric targeting and prolonged retention in vivo, effectively suppressing H. pylori. Notably, chitosan N-acetylglucosamine units bound the bacterial adhesin BabA, further promoting targeted accumulation and antibacterial efficacy. Oral treatment reduced bacterial colonization, alleviated gastric inflammation, and facilitated mucosal healing while preserving microbial balance. This work presents a computationally guided strategy for engineering stable, targeted herbal nanotherapeutics against H. pylori infection.