Abstract：
As a noninvasive treatment modality, high-intensity focused ultrasound (HIFU)-induced antitumor immune responses play a vital role in surgery prognosis. However, limited response intensity largely hinders postoperative immunotherapy. Herein, a hypoxia-specific metal-organic framework (MOF) nanosystem, coordinated by Fe3+, hypoxic-activated prodrug AQ4N, and IDO-1 signaling pathway inhibitor NLG919, is developed for the potentiating immunotherapy of HIFU surgery. The loaded AQ4N enhances the photoacoustic imaging effects to achieve accurate intraoperative navigation. Within the HIFU-established severe hypoxic environment, AQ4N is activated sequentially, following which it cooperates with Fe3+ to effectively provoke immunogenic cell death. In addition, potent NLG919 suppresses IDO-1 activity and degrades the immunosuppressive tumor microenvironment aggravated by postoperative hypoxia. In vivo studies demonstrate that the MOF-mediated immunotherapy greatly inhibits the growth of primary/distant tumors and eliminates lung metastasis. This work establishes a robust delivery platform to improve immunotherapy and the overall prognosis of HIFU surgery with high specificity and potency.
摘要：
作为一种无创治疗方式，高强度聚焦超声（HIFU）诱导的抗肿瘤免疫反应对手术预后起着至关重要的作用。然而,有限的反应强度在很大程度上阻碍了术后免疫治疗。在这里，缺氧特异性金属有机框架(MOF)纳米系统，由Fe3+协调，低氧激活前药AQ4N,和IDO-1信号通路抑制剂NLG919被开发用于增强HIFU手术的免疫治疗。加载的AQ4N增强了光声成像效果，实现了精确的术中导航。在HIFU建立的严重缺氧环境中，AQ4N被顺序激活，随后它与Fe3+合作以有效地引起免疫原性细胞死亡。此外,有效的NLG919抑制IDO-1活性并降解因术后缺氧而加重的免疫抑制肿瘤微环境。体内研究表明，MOF介导的免疫疗法极大地抑制了原发性/远处肿瘤的生长并消除了肺转移。这项工作建立了一个强大的递送平台，以改善免疫治疗和HIFU手术的整体预后，具有高特异性和效力。
