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

## TL;DR

This paper reviews how botulinum neurotoxins use nontoxic proteins to survive in the gut and spread through the body after being ingested.

## Contribution

It provides new insights into the molecular strategies of botulinum neurotoxin complexes for systemic dissemination.

## Key findings

- BoNTs bind to NTNH factors to interact with OrfXs/P47 or HAs for systemic spread.
- NTNH anchors to HA70 or protease-activated OrfX2, enhancing oral toxicity.
- The review highlights divergent pathways for intestinal absorption of BoNTs.

## Abstract

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.