Outer membrane vesicle-wrapped manganese nanoreactor for augmenting cancer metalloimmunotherapy through hypoxia attenuation and immune stimulation

Abstract

Tumor hypoxia, high oxidative stress, and low immunogenic create a deep-rooted immunosuppressive microenvironment, posing a major challenge to the therapeutic efficiency of cancer immunotherapy for solid tumor. Herein, an intelligent nanoplatform responsive to the tumor microenvironment (TME) capable of hypoxia relief and immune stimulation has been engineered for efficient solid tumor immunotherapy. The MnO₂@OxA@OMV nanoreactor, enclosing bacterial-derived outer membrane vesicles (OMVs)-wrapped MnO₂ nanoenzyme and the immunogenic cell death inducer oxaliplatin (OxA), demonstrated intrinsic catalase-like activity within the TME, which effectively catalyzed the endogenous H₂O₂ into O₂ to enable a prolonged oxygen supply, thereby alleviating the tumor's oxidative stress and hypoxic TME, and expediting OxA release. The combinational action of OxA-caused ICD effect and Mn²⁺ from nanoreactor enabled the motivation of the cGAS-STING pathway to significantly improve the activation of STING and dendritic cells (DCs) maturation, resulting in metalloimmunotherapy. Furthermore, the immunostimulant OMVs played a crucial role in promoting the infiltration of activated CD8⁺T cells into the solid tumor. Overall, the nanoreactor offers a robust platform for solid tumor treatment, highlighting the significant potential of combining relief from tumor hypoxia and immune stimulation for metalloimmunotherapy. STATEMENT OF SIGNIFICANCE: A tailor-made nanoreactor was fabricated by enclosing bacterial-derived outer membrane vesicles (OMVs) onto MnO₂ nanoenzyme and loading with immunogenic cell death inducer oxaliplatin (OxA) for tumor metalloimmunotherapy. The nanoreactor possesses intrinsic catalase-like activity within the tumor microenvironment, which effectively enabled a prolonged oxygen supply by catalyzing the conversion of endogenous H₂O₂ into O2, thereby alleviating tumor hypoxia and expediting OxA release. Furthermore, the TME-responsive release of nutritional Mn²⁺ sensitized the cGAS-STING pathway and collaborated with OxA-induced immunogenic cell death (ICD). Combing with immunostimulatory OMVs enhances the uptake of nanoreactors by DCs and promotes the infiltration of activated CD8⁺T cells. This nanoreactor offers a robust platform for solid tumor treatment, highlighting the significant potential of combining relief from tumor hypoxia and immune stimulation for metalloimmunotherapy.

Keywords: Cancer metalloimmunotherapy; Immunogenic cell death; Nanoreactor; Outer membrane vesicle; Tumor hypoxia; cGAS-STING pathway.