Bacterial Expression of Promelittin for Safe and Effective Tumor Therapy.

Bacteria-based tumor therapy has attracted much attention due to its unique mechanism and abundant application. With the rapid development of synthetic biology, utilizing gene technology to make bacteria express therapeutic agents has greatly innovated bacterial therapy paradigms. Herein, we constructed an Escherichia coli expressing promelittin protein system based on the Trojan horse strategy, which limited the toxicity of melittin through the fusion protein during melittin expression. After targeted colonization of bacteria in tumor tissues, promelittin was activated by matrix metalloproteinase, followed by causing tumor cell death through a membrane-lytic mechanism. Additionally, the released cytolytic melittin in turn killed the maternal bacteria, eliminating safety hazards and triggering host immunity. Detailed experiments revealed that the bacteria expressing the promelittin system could significantly inhibit the proliferation and metastasis of primitive tumors in a CT26-bearing mice model. This study sheds insights into the development of bacteria-based synergistic tumor therapy.

Copper-Based Metal-Organic Framework Induces NO Generation for Synergistic Tumor Therapy and Antimetastasis Activity.

The interaction between platelets and circulating tumor cells (CTCs) contributes to distal tumor metastasis by protecting CTCs from immunological assault and shear stress, which can be disrupted by nitric oxide (NO) through inhibiting platelet-mediated adhesion. To eradicate primitive tumors and inhibit CTC-based pulmonary metastasis, a novel biomimetic nanomedicine (mCuMNO) is designed by encapsulating Cu+ -responsive S-nitrosoglutathione as a NO donor into a copper-based metal-organic framework (CuM). This work discovers that mCuMNO can target tumor regions and deplete local glutathione (GSH) to reduce Cu2+ to Cu+ , followed by triggering NO release and hydroxyl radicals (·OH) production, thereby interrupting platelet/CTC interplay and contributing to chemodynamic therapy. Detailed studies demonstrate that mCuMNO exhibits high efficiency and safety in tumor therapy and antimetastasis activity, sheding new light on the development of CuM-based tumor synthetic therapy.

Bacteria-mediated tumor immunotherapy via photothermally-programmed PD1 expression.

The special microenvironment of a solid tumor promotes the orientation and colonization of facultative anaerobes. Intratumoral bacterial infection disrupts the local vascular system to form a thrombus, resulting in darkened tumor sites and enhanced near-infrared absorption. Based on this, we constructed thermally-induced bacteria (TIB) to express programmed cell death protein 1 (PD1) at tumor tissue sites. Under laser irradiation, the elevated temperature at the tumor site not only caused damage to tumor cells but also induced the expression of PD1. Expressed PD1 bound to the ligand of PD1 (PD-L1) on the tumor cell surface and facilitated its internalization and reduction, thereby relieving immune suppression in the tumor microenvironment. Through the combined effects of photothermal therapy and immune activation, the ingenious TIB@PD1 approach greatly inhibited the proliferation and metastasis of tumor cells. Therefore, bacteria-based photothermal immunotherapy represents an appealing method for tumor therapy with good specificity and selectivity.

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

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.