A programmable encapsulation system improves delivery of therapeutic bacteria in mice

作者：Tetsuhiro Harimoto, Jaeseung Hahn, Yuyu Chen, Jongwon Im, Joanna T. Zhang, Nicholas Y. Hou, Fangda Li, Courtney Coker, Kelsey J. Gray, Nicole Harr, Sreyan Chowdhury, Kelly Pu, Clare A. Nimura, Nicholas Arpaia, Kam W. Leong, Tal Danino · 发表于：Nature Biotechnology · 年份：2022 · DOI：10.1038/s41587-022-01244-y · 被引用次数：267 · 研究领域：Cancer Research and Treatments、Bacteriophages and microbial interactions、Nanoplatforms for cancer theranostics

Living bacteria therapies have been proposed as an alternative approach to treating a broad array of cancers. In this study, we developed a genetically encoded microbial encapsulation system with tunable and dynamic expression of surface capsular polysaccharides that enhances systemic delivery. Based on a small RNA screen of capsular biosynthesis pathways, we constructed inducible synthetic gene circuits that regulate bacterial encapsulation in Escherichia coli Nissle 1917. These bacteria are capable of temporarily evading immune attack, whereas subsequent loss of encapsulation results in effective clearance in vivo. This dynamic delivery strategy enabled a ten-fold increase in maximum tolerated dose of bacteria and improved anti-tumor efficacy in murine models of cancer. Furthermore, in situ encapsulation increased the fraction of microbial translocation among mouse tumors, leading to efficacy in distal tumors. The programmable encapsulation system promises to enhance the therapeutic utility of living engineered bacteria for cancer.