From Gut to Systemic Circulation: Molecular Strategies of Botulinum Neurotoxin Complexes

Botulinum neurotoxins (BoNTs), among the most potent biological toxins, rely on co-produced nontoxic proteins to survive harsh gastrointestinal conditions and achieve efficient systemic dissemination after oral exposure. Recent structural and functional studies have revealed how BoNTs bind to the nontoxic non-hemagglutinin (NTNH) factors to engage in interactions with either OrfXs/P47 or hemagglutinins (HAs) components for systemic dissemination. This review synthesizes recent findings that elucidate the molecular basis of NTNH-specific anchoring to the HA70 triskelion-like element or to the host protease-activated form of OrfX2, thereby highlighting divergent pathways that enhance oral toxicity. We also discuss current perspectives on the molecular mechanisms through which BoNTs, in cooperation with associated nontoxic proteins, are absorbed from the intestine.