Bacteria‐Elicited Specific Thrombosis Utilizing Acid‐Induced Cytolysin A Expression to Enable Potent Tumor Therapy

Abstract

Given the special microenvironment of solid tumors, live microorganisms have emerged as drug delivery vehicles and therapeutic agents. Here, an acid-induced therapeutic platform is constructed using attenuated Escherichia coli to express the cytolysin A protein. The bacteria can target and colonize tumor tissues without causing notable host toxicity. Bacterial infection can disrupt blood vessels and trigger thrombosis in tumor tissues, resulting in the cut-off of nutrient supply to tumor cells and the arrest of tumor growth. The expression of cytolysin A induced by the acidic tumor microenvironment further strengthens thrombosis and provides a complementary therapeutic option due to its pore-forming function. In a xenograft mouse tumor model, this strategy reduces tumor proliferation by 79% and significantly prevents tumor metastasis, thus paving a new avenue for bacteria-based tumor therapy.

Coupling Probiotics with 2D CoCuMo‐LDH Nanosheets as a Tumor‐Microenvironment‐Responsive Platform for Precise NIR‐II Photodynamic Therapy

“…[30][31][32][33] Recently, bacteria-based tumor therapeutic platforms have been developed for tumor targeted therapy since bacteria possess excellent tumor-targeting ability through hypoxia tropism, chemotaxis, and immune escape. [34][35][36][37] Moreover, bacteria can further improve tumor treatment outcomes through consuming lactic acid to reduce multidrug resistance to chemotherapy drugs, increasing localized H 2 O 2 generation to enhance chemodynamic therapy (CDT), inducing thrombus formation to amplify photothermal therapy, or improving antitumor immune responses to promote immunotherapy. [38][39][40][41] For example, a Fenton-like bacterial bioreactor composed of Fe 3 O 4 nanoparticles and Escherichia coli MG1655 engineered with respiratory chain enzyme II overexpression was designed for CDT, which could colonize in tumor regions and then produce H 2 O 2 through bacterial respiration for subsequent in situ catalyzation of Fenton-like reaction.…”

Recent advances in bacterial therapeutics based on sense and response

“…However, the application of bacteria was limited because of their toxicity. With the rapid development of synthetic biology, many strains have been engineered to control their safety and once again entered the stage of tumor treatment, such as Escherichia coli 14 , 15 , 16 , Salmonella typhimurium 17 , 18 , 19 , and Listeria monocytogenes 20 , 21 , 22 . Based on the colonization in tumor tissue, engineered bacteria can perceive the external conditions, and responsively synthesize or release drugs to improve the targeting delivery of drugs, reduce the damage to normal tissues, and provide a unique idea for tumor-targeted therapies.…”

Bacterial Expression of Promelittin for Safe and Effective Tumor Therapy

“…13 The mechanisms underlying the apoptosis of tumor cells and the activation of the immune system remain to be clarified but are thought to involve the bacterial oncolysis and generation of cytokines. 14,15 Compared with inactive nanoparticles, the complex physiological functions of bacteria also make them good therapeutic vectors for drug delivery in tumor therapy. 16 With the vigorous development of synthetic biology over the past two decades, bacteria-based tumor therapy presents more efficacy and diversity.…”

“…Nowadays, bacteria-based tumor therapy with a long history has received increasing attention in recent years. , Owing to the tumor microenvironment nature of immunosuppression and hypoxia, facultative anaerobes and obligate anaerobes preferentially home to and colonize tumor cores and locally affect tumor growth . The mechanisms underlying the apoptosis of tumor cells and the activation of the immune system remain to be clarified but are thought to involve the bacterial oncolysis and generation of cytokines. , Compared with inactive nanoparticles, the complex physiological functions of bacteria also make them good therapeutic vectors for drug delivery in tumor therapy . With the vigorous development of synthetic biology over the past two decades, bacteria-based tumor therapy presents more efficacy and diversity. − The bacterial genome is simple and easy to be engineered .…”