<br>基于逻辑“与门电路”的 Gasdermin 蛋白表达纳米平台诱导肿瘤特异性焦亡以增强癌症免疫治疗,ACS Nano

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基于逻辑“与门电路”的 Gasdermin 蛋白表达纳米平台诱导肿瘤特异性焦亡以增强癌症免疫治疗
ACS Nano ( IF 15.8 ) Pub Date : 2024-02-20 , DOI: 10.1021/acsnano.3c09405
Xiaoxi Wang ₁ , Wenyan Zhang ₁ , Yan Wang ₁ , Xueqin Zhu ₁ , Zimai Liu ₁ , Meiyi Liu ₁ , Zixian Wu ₁ , Bingyu Li ₁ , Sijia Liu ₁ , Shixin Liao ₁ , Pingping Zhu _{1,

2} , Benyu Liu ₂ , Chong Li _{3,

4} , Yongchao Wang ₁ , Zhenzhen Chen _{1,

5,

6}

Affiliation

Gasdermin 蛋白介导的细胞焦亡在癌症免疫治疗中显示出巨大的潜力。然而，gasdermin蛋白的低表达和非特异性细胞焦亡的全身毒性限制了其临床应用。在这里，我们设计了一种合成生物学策略来构建肿瘤特异性焦亡诱导纳米平台M-CNP/Mn@pPHS，其中将焦亡诱导质粒（pPHS）加载到锰（Mn）掺杂的碳酸钙纳米颗粒上并包裹在肿瘤来源的细胞膜中。 M-CNP/Mn@pPHS 显示出有效的肿瘤靶向能力。被肿瘤细胞内化后，M-CNP/Mn@pPHS在酸性内体环境中降解，使得质粒pPHS能够有效地逃逸内体。为了触发肿瘤特异性焦亡，pPHS按照逻辑“与门电路”策略设计，以Hif-1α和Sox4作为两个输入信号，以gasdermin D诱导的焦亡作为输出信号。只有在Hif-1α和Sox4同时高表达的细胞中才会表达输出信号gasdermin D。由于Hif-1α和Sox4均在肿瘤细胞中特异性表达，M-CNP/Mn@pPHS诱导gasdermin D的肿瘤特异性表达，从而诱导细胞焦亡，引发有效的免疫反应，且全身毒性很小。从纳米平台释放的Mn ²⁺通过刺激cGAS-STING途径进一步增强抗肿瘤免疫反应。因此，M-CNP/Mn@pPHS 有效抑制肿瘤生长，体内肿瘤消退率为 79.8%。我们证明，这种基于逻辑“与门电路”的gasdermin纳米平台是一种有前途的策略，用于诱导肿瘤特异性细胞焦亡，且全身毒性很小。

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Logic “AND Gate Circuit”-Based Gasdermin Protein Expressing Nanoplatform Induces Tumor-Specific Pyroptosis to Enhance Cancer Immunotherapy

Pyroptosis mediated by gasdermin protein has shown great potential in cancer immunotherapies. However, the low expression of gasdermin proteins and the systemic toxicity of nonspecific pyroptosis limit its clinical application. Here, we designed a synthetic biology strategy to construct a tumor-specific pyroptosis-inducing nanoplatform M-CNP/Mn@pPHS, in which a pyroptosis-inducing plasmid (pPHS) was loaded onto a manganese (Mn)-doped calcium carbonate nanoparticle and wrapped in a tumor-derived cell membrane. M-CNP/Mn@pPHS showed an efficient tumor targeting ability. After its internalization by tumor cells, the degradation of M-CNP/Mn@pPHS in the acidic endosomal environment allowed the efficient endosomal escape of plasmid pPHS. To trigger tumor-specific pyroptosis, pPHS was designed according to the logic “AND gate circuit” strategy, with Hif-1α and Sox4 as two input signals and gasdermin D induced pyroptosis as output signal. Only in cells with high expression of Hif-1α and Sox4 simultaneously will the output signal gasdermin D be expressed. Since Hif-1α and Sox4 are both specifically expressed in tumor cells, M-CNP/Mn@pPHS induces the tumor-specific expression of gasdermin D and thus pyroptosis, triggering an efficient immune response with little systemic toxicity. The Mn²⁺ released from the nanoplatform further enhanced the antitumor immune response by stimulating the cGAS-STING pathway. Thus, M-CNP/Mn@pPHS efficiently inhibited tumor growth with 79.8% tumor regression in vivo. We demonstrate that this logic “AND gate circuit”-based gasdermin nanoplatform is a promising strategy for inducing tumor-specific pyroptosis with little systemic toxicity.

更新日期：2024-02-20

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