Engineered radiation-sensitive probiotic for synergistic tumor cell cycle blockade and immunomodulation to potentiate radio-immunotherapy in pancreatic cancer

In this study, an engineered probiotic (denoted as CBB) was rationally designed for enhanced radio-immunotherapy through tumor cell cycle blockade and radiation sensitization. The anaerobic Clostridium butyricum (CB) was surface modified with bismuth nanoparticles-coordinated black phosphorus nanosheets (BPs-Bi) through MMP-2 sensitive peptide to prepare the engineered probiotic CBB. Due to the hypoxia tropism of CB, CBB could actively target and penetrate into deep pancreatic tumors, in favor of the enhanced tumor accumulation and distribution of BPs-Bi. Within tumor, BPs-Bi trapped tumor cells in radio-sensitive G2/M phase by regulating CDK1 and PCNA, while its high conductivity and large specific area helped electron transfer to amplify Bi-mediated radio-toxicity via boosting the generation of ROS to damage tumor cells. Worth noted, radiotherapy induced the release of damage-associated molecular patterns (DAMPs) from tumor cells, and concurrently triggered bacteria death to secrete bacterial antigens, which further provoked robust antitumor immune responses for local control and metastasis remission of malignant pancreatic tumors, highlighting new opportunities for pancreatic cancer radio-immunotherapy.