Glutathione-responsive self-assembling peptide-coated Salmonella for antitumor therapy

The clinical translation of bacteria-mediated immunotherapy has been hindered by severe systemic toxicity due to off-target bacterial colonization. To address these limitations, we developed a glutathione (GSH)-responsive self-assembling peptide that forms a nanofibrous coating on Salmonella typhimurium, enabling spatiotemporal control over bacterial activity. The peptide binds lipopolysaccharides on the bacterial surface via electrostatic and hydrogen bonding interactions, forming a stable protective layer that shields immunogenic epitopes. In the reductive tumor microenvironment, elevated GSH levels trigger disulfide bond cleavage, resulting in disassembly of the peptide shell and controlled bacterial release at tumor sites. In vivo, 10 μM and 20 μM peptide coatings enhanced tumor accumulation by ∼2.5- and ∼ 1.5-fold, respectively, primarily by enhancing tumor retention and reducing pre-targeting immune clearance. This was accompanied by an increase in tumor-infiltrating neutrophils, key effectors in tumor regression. Importantly, this occurred with markedly reduced systemic inflammation and organ toxicity compared with unmodified bacteria. This strategy offers a promising platform for improving the precision and safety of bacterial immunotherapy, advancing its potential for clinical application in cancer treatment.