Engineered bacterial membrane vesicle as safe and efficient nano-heaters to reprogram tumor microenvironment for enhanced immunotherapy

The immunosuppressive tumor microenvironment (TME) in solid tumors often impedes the efficacy of immunotherapy. Bacterial outer membrane vesicles (OMVs), as a promising cancer vaccine that can potently stimulate immune responses, have garnered interest as a potential platform for cancer therapy. However, the low yield of OMVs limits their utilization. To address this limitation, we developed a novel approach to synthesize OMV-like multifunctional synthetic bacterial vesicles (SBVs) by pretreating bacteria with ampicillin and lysing them through sonication. Compared to OMVs, the yield of SBVs increased by 40 times. Additionally, the unique synthesis process of SBVs allows for the encapsulation of bacterial intracellular contents, endowing SBVs with the capability of delivering catalase (CAT) for tumor hypoxia relief and activating the host cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway. To overcome the toxicity of lipopolysaccharide (LPS) on the SBVs surface, we decorated SBVs with a biocompatible polydopamine (PDA) shell, which allowed TME reprogramming using SBVs to be conducted without adverse side effects. Additionally, the photosensitizer indocyanine green (ICG) was loaded into the PDA shell to induce immunogenic cell death and further improve the efficacy of immunotherapy. In summary, the SBVs-based therapeutic platform SBV@PDA/ICG (SBV@P/I) can synergistically elicit safe and potent tumor-specific antitumor responses through combined immunotherapy and phototherapy. SBV@P/I regulates the tumor microenvironment (TME), kills tumor cells and releases tumor-associated antigens (TAAs). Activated dendritic cells present TAAs and stimulate effector T cells to generate specific anti-tumor immune responses. [Display omitted] •Synthesized high-yield multifunctional SBVs have the capability to alleviate hypoxia and modulate immune cell activation.•Utilizing the PDA/ICG shell reduces the in vivo toxicity of SBVs and endows them with photothermal therapy potential.•Synergistic phototherapy and immunotherapy showed enhanced efficacy and long-term biosafety in vivo.