Intratumoural bacteria represent a promising drug-free strategy in cancer therapy. Here we demonstrate that a tumour-resident bacterial consortium-Proteus mirabilis (A-gyo) and Rhodopseudomonas palustris (UN-gyo)-in a precise 3:97 ratio (A-gyo:UN-gyo), exhibits potent antitumour efficacy independent of immune cell infiltration. In both immunocompetent and immunocompromised mouse models, including human tumour xenografts, intravenous administration of the bacterial consortium led to complete tumour remission, prolonged survival, and no observable systemic toxicity or cytokine release syndrome. Genomic and phenotypic analyses revealed A-gyo's unique non-pathogenic profile and impaired motility, while UN-gyo modulated A-gyo's biogenic activity, enhanced safety and promoted cancer-specific transformation. Mechanistically, the bacterial consortium triggered selective intratumoural thrombosis and vascular collapse-supported by cytokine induction, fibrin deposition and platelet aggregation-culminating in widespread tumour necrosis. The consortium also proliferated within tumours, formed biofilms and exerted direct oncolytic effects. This natural bacterial synergy-achieved without genetic engineering-offers a self-regulating and controllable strategy for safe, tumour-targeted therapy.

The utilization of gut microbiota in cancer therapy has attracted considerable attention as an emerging therapeutic frontier. In this study, we systematically evaluated the antitumor effects of nine bacterial strains isolated from the intestines of amphibians (Dryophytes japonicus and Cynops pyrrhogaster) and a reptile (Takydromus tachydromoides). Among the isolates, Ewingella americana exhibited remarkably potent cytotoxic activity with selective tumor-targeting ability characteristic of facultative anaerobic bacteria. Mechanistic investigations revealed that E. americana functions through a dual-action mechanism: direct tumor cell killing and robust activation of host immunity, leading to enhanced T cell, neutrophil, and B cell-mediated tumor attack. Treatment with E. americana significantly outperformed standard therapies, including anti-PD-L1 antibody and doxorubicin, in tumor regression studies. Importantly, comprehensive safety evaluations in murine models demonstrated that the gut-derived E. americana strain exhibits minimal pathogenicity and exerts no significant adverse effects at therapeutically effective doses, contrasting favorably with genetically modified bacterial therapeutics. Comparative analysis revealed superior therapeutic efficacy of E. americana over conventional treatments while maintaining an excellent safety profile. These findings suggest that gut microbiomes of lower vertebrates harbor numerous uncharacterized bacterial species with exceptional therapeutic potential. Our study establishes a foundation for developing naturally occurring, non-pathogenic bacterial therapeutics and underscores the critical importance of microbial biodiversity in advancing cancer treatment strategies.

Establishing drug delivery systems (DDSs) for transporting drugs from peripheral tissues to the brain is crucial for treating central nervous system diseases. We previously reported the interactions of (1) KS-133, a selective antagonist peptide, with vasoactive intestinal peptide receptor 2 (VIPR2), a drug target for schizophrenia, and (2) KS-487, a selective binding peptide, with the cluster IV domain of low-density lipoprotein receptor-related protein 1 (LRP1), which is involved in crossing the blood-brain barrier. We developed a novel DDS-based strategy for treating schizophrenia using KS-487 as a brain-targeting peptide and KS-133 as a drug. Dibenzocyclooctyne-KS-487 was conjugated with N3-indocyanine green (ICG) using a click reaction and administered intravenously into mice. Fluorescence was clearly observed from ICG in the brains of the mice. Nanoparticles (NPs) encapsulating ICG and displaying KS-487 were prepared and subcutaneously administered to mice, resulting in a significant accumulation of ICG in the brain. Pharmacokinetic analysis of NPs containing KS-133 and displaying KS-487 (KS-133/KS-487 NPs) revealed the time-dependent transport of KS-133 into the brain. KS-133/KS-487 NPs were subcutaneously administered to mouse models of schizophrenia, which significantly improved cognitive dysfunction. This is the first study to demonstrate the potential therapeutic efficacy of a multifunctionalized multipeptide NP in inhibiting VIPR2.