Manipulating Offense and Defense Signaling to Fight Cold Tumors with Carrier-Free Nanoassembly of Fluorinated Prodrug and siRNA,Advanced Materials

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Manipulating Offense and Defense Signaling to Fight Cold Tumors with Carrier-Free Nanoassembly of Fluorinated Prodrug and siRNA
Advanced Materials ( IF 27.4 ) Pub Date : 2022-08-02 , DOI: 10.1002/adma.202203019
Pengkai Wu _{1,

2} , Haitian Zhang _{1,

2} , Meiling Sun ₁ , Shuai Mao ₁ , Qifeng He ₁ , Yuze Shi ₁ , Yexuan Deng ₁ , Zhongjun Dong ₂ , Qingxiang Xu ₁ , Chen Zhao ₃ , Wenjie Zhang _{1,

2} , Beicheng Sun _{1,

2}

Affiliation

Chemoimmunotherapy has shown great potential to activate an immune response, but the immunosuppressive microenvironment associated with T cell exhaustion remains a challenge in cancer therapy. The proper immune-modulatory strategy to provoke a robust immune response is to simultaneously regulate T-cell exhaustion and infiltration. Here, a new kind of carrier-free nanoparticle is developed to simultaneously deliver chemotherapeutic drug (doxorubicin, DOX), cytolytic peptide (melittin, MPI), and anti-TOX small interfering RNA (thymocyte selection-associated high mobility group box protein, TOX) using a fluorinated prodrug strategy. In this way, the enhanced immunogenic cell death (ICD) induced by the combination of DOX and MPI can act as “offense” signaling to increase CD8⁺ T-cell infiltration, while the decreased TOX expression interfered with siTOX can serve as “defense” signaling to mitigate CD8⁺ T-cell exhaustion. As a result, the integration of DOX, MPI, and siTOX in such a bifunctional system produced a potent antitumor immune response in liver cancer and metastasis, making it a promising delivery platform and effective strategy for converting “cold” tumors into “hot” ones.

中文翻译：

使用氟化前药和 siRNA 的无载体纳米组装来操纵攻防信号以对抗感冒肿瘤

化学免疫疗法已显示出激活免疫反应的巨大潜力，但与 T 细胞耗竭相关的免疫抑制微环境仍然是癌症治疗的挑战。激发强大免疫反应的适当免疫调节策略是同时调节 T 细胞耗竭和浸润。在这里，开发了一种新型无载体纳米颗粒，可同时递送化疗药物（阿霉素，DOX）、溶细胞肽（蜂毒肽，MPI）和抗 TOX 小干扰 RNA（胸腺细胞选择相关的高迁移率组盒蛋白，TOX ) 使用氟化前药策略。这样，由 DOX 和 MPI 联合诱导的增强免疫原性细胞死亡 (ICD) 可以作为“进攻”信号传导，增加 CD8 ⁺T 细胞浸润，而减少的 TOX 表达干扰 siTOX 可以作为“防御”信号，以减轻 CD8 ⁺ T 细胞耗竭。因此，DOX、MPI 和 siTOX 在这种双功能系统中的整合在肝癌和转移中产生了有效的抗肿瘤免疫反应，使其成为将“冷”肿瘤转化为“热”肿瘤的有前景的递送平台和有效策略.

更新日期：2022-08-02

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