A programmable encapsulation system improves delivery of therapeutic bacteria in mice

Abstract

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.

Decorating Bacteria with Triple Immune Nanoactivators Generates Tumor‐Resident Living Immunotherapeutics

“…Interestingly, we found a significant increase of the percentage of CD44 + CD62L − cells in the spleen of mice treated with EcN, EcN@P, EcN@PO, and EcN@PPO (Figure S14), indicating the promotion of effector memory T cells that are able to produce an immune memory effect [51, 52] . Mice treated with EcN@PPO_NIR also exhibited the highest expressions of MHC I‐OVA and MHC II on DCs as well as decreased ratio of Tregs (CD4 + Foxp3 + ) and the highest ratio of CD8 + , CD8 + Ki67 + , and CD8 + TET + cells in the spleen (Figure S15), demonstrating the elicitation of a strong systemic antitumor immunity that may inhibit the growth of distal tumors [53] . It should be mentioned that local injection of EcN@PPO led to no obvious damage to major organs, such as the liver, kidney, and spleen (Figure S16).…”

Magnetically steerable bacterial microrobots moving in 3D biological matrices for stimuli-responsive cargo delivery

“…Therefore, both in bacteria-mediated and biohybrid cancer therapies, it is essential to establish an optimum balance between the immune stimulation and the safety of the therapy and to provide a “safety” tool, which could be achieved by either genetically engineering the bacteria or biohybridizing with immune compatibility. In the literature, various genetic engineering approaches have been used to improve the safety of bacterial therapies, such as attenuation of pathogenic bacterial species [including various Salmonella ( 53 – 55 ) and E. coli strains ( 56 , 57 )], termination switches ( 14 , 58 , 59 ), and immune evasion ( 60 ). Current bacteria-mediated cancer therapy clinical trials ( 14 ) include Salmonella typhimurium VNP20009 (NCT01099631), an attenuated strain of Salmonella to improve the safety of therapy; SYNB1891 (NCT04167137), a probiotic strain of E. coli Nissle engineered to synthesize Stimulator of Interferon Genes (STING) agonist cyclic di-adenosine monophosphate; and Listeria monocytogenes (NCT02325557), which is commonly used to express and secrete antigen-adjuvant fusion proteins.…”

Decorating Bacteria with Triple Immune Nanoactivators Generates Tumor‐Resident Living Immunotherapeutics

“…Chemie ure S15), demonstrating the elicitation of a strong systemic antitumor immunity that may inhibit the growth of distal tumors. [53] It should be mentioned that local injection of EcN@PPO led to no obvious damage to major organs, such as the liver, kidney, and spleen (Figure S16). A single injection of EcN@PPO plus laser irradiation stimulated potent intratumoral immune responses including the repolarization of TAMs, the maturation of DCs, and the crosspriming of antigen-specific cytotoxic T lymphocytes.…”