Chen Beibei, Guo Kangli, Zhao Xiaoyi, Liu Zhiwen, Xu Chen, Zhao Nana, Xu Fu-Jian
State Key Laboratory of Chemical Resource Engineering Beijing University of Chemical Technology Beijing China.
Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Beijing Laboratory of Biomedical Materials Beijing University of Chemical Technology Beijing China.
Exploration (Beijing). 2023 Jul 27;3(6):20220140. doi: 10.1002/EXP.20220140. eCollection 2023 Dec.
Carbon monoxide (CO) gas therapy demonstrates great potential to induce cancer cell apoptosis and antitumor immune responses, which exhibits tremendous potential in cancer treatment. However, the therapeutic efficacy of CO therapy is inhibited by the immunosuppressive tumor microenvironment (TME). Herein, a facile strategy is proposed to construct hollow-structured rough nanoplatforms to boost antitumor immunity and simultaneously reverse immunosuppression by exploring intrinsic immunomodulatory properties and morphological optimization of nanomaterials. The TME-responsive delivery nanosystems (M-RMH) are developed by encapsulating the CO prodrug within hollow rough MnO nanoparticles and the subsequent surface functionalization with hyaluronic acid (HA). Rough surfaces are designed to facilitate the intrinsic properties of HA-functionalized MnO nanoparticles (RMH) to induce dendritic cell maturation and M1 macrophage polarization by STING pathway activation and hypoxia alleviation through enhanced cellular uptake. After TME-responsive degradation of RMH, controlled release of CO is triggered at the tumor site for CO therapy to activate antitumor immunity. More importantly, RMH could modulate immunosuppressive TME by hypoxia alleviation. After the combination with aPD-L1-mediated checkpoint blockade therapy, robust antitumor immune responses are found to inhibit both primary and distant tumors. This work provides a facile strategy to construct superior delivery nanosystems for enhanced CO/immunotherapy through efficient activation of antitumor immune responses and reversal of immunosuppression.
一氧化碳（CO）气体疗法在诱导癌细胞凋亡和抗肿瘤免疫反应方面显示出巨大潜力，在癌症治疗中展现出极大的前景。然而，CO疗法的治疗效果受到免疫抑制性肿瘤微环境（TME）的抑制。在此，我们提出了一种简便的策略，通过探索纳米材料的内在免疫调节特性和形态优化，构建中空结构的粗糙纳米平台，以增强抗肿瘤免疫力并同时逆转免疫抑制。通过将CO前药封装在中空粗糙的MnO纳米颗粒中，并随后用透明质酸（HA）进行表面功能化，开发了TME响应性递送纳米系统（M-RMH）。粗糙表面的设计有助于HA功能化的MnO纳米颗粒（RMH）通过激活STING途径和通过增强细胞摄取缓解缺氧来诱导树突状细胞成熟和M1巨噬细胞极化的内在特性。RMH在TME响应性降解后，在肿瘤部位触发CO的控释以进行CO疗法，从而激活抗肿瘤免疫力。更重要的是，RMH可以通过缓解缺氧来调节免疫抑制性TME。与aPD-L1介导的检查点阻断疗法联合使用后，发现强大的抗肿瘤免疫反应可抑制原发性和远处肿瘤。这项工作提供了一种简便的策略，通过有效激活抗肿瘤免疫反应和逆转免疫抑制来构建用于增强CO/免疫疗法的优质递送纳米系统。
