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Glycan-modified cellular nanosponges for enhanced neutralization of botulinum toxin

Ai, X;Wang, D;Noh, I;Duan, Y;Zhou, Z;Mukundan, N;Fang, RH;Gao, W;Zhang, L;

Botulinum toxin (BoNT) is a potent neurotoxin that poses a significant threat as a biowarfare weapon and a potential bioterrorist tool. Currently, there is a lack of effective countermeasures to combat BoNT intoxication in the event of a biological attack. Here, we report on a novel solution by combining cell metabolic engineering with cell membrane coating nanotechnology, resulting in the development of glycan-modified cellular nanosponges that serve as a biomimetic and broad-spectrum BoNT detoxification strategy. Specifically, we increase the expression levels of gangliosides on THP-1 cells through metabolic engineering, and then collect the modified THP-1 cell membrane and coat it onto synthetic polymeric cores, creating cellular nanosponges that closely mimic host cells. Our findings demonstrate that higher levels of gangliosides on the cellular nanosponges result in greater binding capacities with BoNT. The glycan-modified cellular nanosponges exhibit superior efficacy in neutralizing BoNT cytotoxicity in vitro when compared to their unmodified counterparts. In a mouse model of BoNT intoxication, the glycan-modified cellular nanosponges show more pronounced survival benefits when administered both as a treatment and a preventative regimen. These results highlight the potential of cellular nanosponges, especially when modified with glycans, as a promising countermeasure platform against BoNT and related clostridial toxins.