肿瘤缺氧,高氧化应激,低免疫原性创造了一个根深蒂固的免疫抑制微环境,对肿瘤免疫治疗实体瘤的疗效提出了重大挑战。在这里,能够缓解缺氧和免疫刺激的对肿瘤微环境(TME)敏感的智能纳米平台已被设计用于有效的实体瘤免疫治疗.MnO2@OxA@OMV纳米反应器,包裹细菌来源的外膜囊泡(OMV)包裹的MnO2纳米酶和免疫原性细胞死亡诱导剂奥沙利铂(OxA),在TME内表现出固有的过氧化氢酶样活性,有效地将内源性H2O2催化成O2,从而延长氧气供应,从而减轻肿瘤的氧化应激和缺氧TME,加快OxA的释放。OxA引起的ICD效应和来自纳米反应器的Mn2+的组合作用使cGAS-STING途径的动机能够显着提高STING的激活和树突状细胞(DC)成熟,导致金属免疫疗法。此外,免疫刺激剂OMV在促进活化的CD8+T细胞浸润到实体瘤中起着至关重要的作用。总的来说,纳米反应器为实体瘤治疗提供了一个强大的平台,强调了将缓解肿瘤缺氧和免疫刺激相结合用于金属免疫疗法的巨大潜力。重要声明:通过将细菌来源的外膜囊泡(OMV)封闭在MnO2纳米酶上并加载免疫原性细胞死亡诱导剂奥沙利铂(OxA)用于肿瘤金属免疫疗法,制造了量身定制的纳米反应器。纳米反应器在肿瘤微环境中具有固有的过氧化氢酶样活性,通过催化内源性H2O2转化为O2,从而有效地延长了氧气供应,从而减轻了肿瘤缺氧并加快了OxA的释放。此外,营养Mn2+的TME响应释放使cGAS-STING途径敏感,并与OxA诱导的免疫原性细胞死亡(ICD)协作。与免疫刺激性OMV结合增强DC对纳米反应器的摄取并促进活化的CD8+T细胞的浸润。这种纳米反应器为实体瘤治疗提供了一个强大的平台,强调了将缓解肿瘤缺氧和免疫刺激相结合用于金属免疫疗法的巨大潜力。
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.