Multimodal oncolytic bacteria by coating with tumor cell derived nanoshells

Microbial therapy has attracted substantial attention for treating cancers given the advances in synthetic bioengineering and the characteristics of bacteria in tumor targeting and colonization. However, the use of bacteria always suffers from unavoidable side effects, rapid clearance by phagocytic cells, low tumor-specific accumulation, and unitary therapeutic modality. Here, we describe the development of carcinoma cell-mimetic bacteria (CCMB), a set of multimodal oncolytic living agents, by coating with tumor cell derived nanoshells. Under external stimulations, intracellularly pre-harbored bacteria are spontaneously coated with an extra membrane by forming apoptotic bodies from invaded tumor cells. Due to the presence of a tumor cell derived membrane, CCMB show low inflammatory reaction, slow bodily elimination, homologous-targeting tumor localization, and a dual modality of antigen-specific immunotherapy and microbial therapy. These findings are supported by desirable tumor regression and metastasis inhibition, along with satisfactory survival rate and stable body weight following a single intravenous injection in multiple mouse models. A single dose of CCMB can also significantly improve the therapeutic response of clinically used anti-programmed death-1 antibodies. Our work discloses how bacteria can be simultaneously endowed with multifaceted exogenous functions by single-cell nanocoating and demonstrates the potency of CCMB for advanced microbial therapy.