锰离子 (Mn2+) 与能够破坏和裂解肿瘤细胞的佐剂结合形成抗肿瘤纳米调节剂，通过级联激活环 GMP-AMP 干扰素基因合酶刺激剂 (cGAS-STING) 途径来增强癌症治疗的免疫功效，这强调了开发抗肿瘤纳米调节剂的重要性，这种纳米调节剂可诱导 DNA 损伤并增强 cGAS-STING 活性，作为未来的一个关键研究方向。方法与结果：我们成功合成了一种抗肿瘤纳米调节剂，具有良好的分散性和生物安全性。这种纳米调节剂是通过在二氧化锰纳米片 (M-NS) 上负载泽布林 (Zeb)（以其免疫原性增强作用而闻名）并使用透明质酸 (HA) 进行靶向表面修饰而设计的。全身循环至肿瘤部位后，Mn2、Zeb和活性氧(ROS)在H和H2O2的催化作用下释放到肿瘤微环境中。这些成分可以直接或间接损伤肿瘤细胞的DNA或线粒体，从而诱导细胞程序性死亡。此外，它们还促进细胞质中双链DNA (dsDNA)的积累，增强cGAS-STING信号通路的激活，促进I型干扰素的产生和促炎细胞因子的分泌。此外，Zeb@MH-NS 还能增强树突状细胞的成熟、细胞毒性 T 淋巴细胞的浸润以及肿瘤部位自然杀伤细胞的募集。这种 HA 修饰的锰基混合纳米调节剂可以通过增强抗肿瘤治疗效果。先天免疫活性，可能为癌症免疫治疗和临床转化提供新方向。© 2024。作者。

Manganese ions (Mn2+) combined with adjuvants capable of damaging and lysing tumor cells form an antitumor nano-modulator that enhances the immune efficacy of cancer therapy through the cascade activation of the cyclic GMP-AMP interferon gene synthase-stimulator (cGAS-STING) pathway, which underscores the importance of developing antitumor nano-modulators, which induce DNA damage and augment cGAS-STING activity, as a critical future research direction. METHODS AND RESULTS: We have successfully synthesized an antitumor nano-modulator, which exhibits good dispersibility and biosafety. This nano-modulator is engineered by loading manganese dioxide nanosheets (M-NS) with zebularine (Zeb), known for its immunogenicity-enhancing effects, and conducting targeted surface modification using hyaluronic acid (HA). After systemic circulation to the tumor site, Mn2+, Zeb, and reactive oxygen species (ROS) are catalytically released in the tumor microenvironment by H+ and H2O2. These components can directly or indirectly damage the DNA or mitochondria of tumor cells, thereby inducing programmed cell death. Furthermore, they promote the accumulation of double-stranded DNA (dsDNA) in the cytoplasm, enhancing the activation of the cGAS-STING signalling pathway and boosting the production of type I interferon and the secretion of pro-inflammatory cytokines. Additionally, Zeb@MH-NS enhances the maturation of dendritic cells, the infiltration of cytotoxic T lymphocytes, and the recruitment of natural killer cells at the tumor site.This HA-modified manganese-based hybrid nano-regulator can enhance antitumor therapy by boosting innate immune activity and may provide new directions for immunotherapy and clinical translation in cancer.© 2024. The Author(s).