Oral probiotics have potential effects for the prevention and treatment of colorectal cancer (CRC). However, the harsh environment and constant changes in the gastrointestinal tract present serious obstacles to the efficient delivery of probiotics to the colon. In this work, a glutathione (GSH)-responsive polymer with anti-cancer properties based on sulfated β-glucan (sGlu) was developed for probiotic encapsulation and targeted delivery. First, sGlu were synthesized using chlorosulfonic acid-dimethylacetamide. Then, 3, 3′-dithiodipropionic acid was successfully grafted onto sGlu following the condensation–polymerization method. Finally, the GSH-responsive polymer and the probiotic Escherichia coliNissle 1917 (EcN) were conjugated using the carbodiimide technique to create the probiotic delivery system (sGlu-COOH@EcN). Here, leveraging the innate hypoxia tropism of EcN and the colon-specific targeting capability of sGlu, sGlu-COOH@EcN was designed to achieve site-specific probiotic delivery. The results from the in vitro studies revealed that sGlu-COOH@EcN showed excellent biocompatibility and effectively enhance the survival rate of EcN in simulated digestive conditions. Meanwhile, excessive production of GSH at the tumor site selectively cleaved disulfide bond in the polymer matrix, leading to localized release of EcN and concomitant generation of sulfhydryl (-SH) groups. The preferential adherence of both EcN and sGlu to colorectal tissues was further enhanced by this GSH-triggered reaction. Additionally, sGlu-COOH synergized with EcN to exert an antioxidant capacity in sGlu-COOH@EcN, which contributing to the amelioration of the tumor microenvironment and enhancement of therapeutic outcomes against CRC. The proposed platform offers an effective and adaptable approach for probiotic-based cancer therapy, combining targeted release, microenvironment modulation, and intrinsic anti-tumor activity.

Keywords:E. coliNissle1917; Sulfated β-glucan; GSH-responsive; Probiotic delivery system; Colorectal cancer