<br>通过分子伴侣介导的嵌合纳米平台自噬靶向降解信号转导和转录激活剂 3,ACS Nano

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通过分子伴侣介导的嵌合纳米平台自噬靶向降解信号转导和转录激活剂 3
ACS Nano ( IF 15.8 ) Pub Date : 2023-12-29 , DOI: 10.1021/acsnano.3c09536
Haohao Song _{1,

2} , Wenping Huang _{1,

3} , Fuhao Jia _{1,

3} , Zhihang Wang _{1,

3} , Jie Zhang _{1,

3} , Ruihao Qian _{1,

3} , Gungjun Nie _{1,

3} , Hai Wang _{1,

3}

Affiliation

分子伴侣介导的自噬（CMA）是一种溶酶体依赖性蛋白水解途径，用于降解胞浆蛋白。然而，利用 CMA 介导的蛋白水解来降解癌症治疗中感兴趣的蛋白质尚未得到广泛应用。在这项研究中，我们开发了一种 CMA 靶向嵌合体 (CMATAC)，可有效且特异性地降解肿瘤细胞中的信号转导和转录激活剂 3 (STAT3)。 CMATAC 由通过接头连接的 STAT3 和热休克同源 70 kDa 蛋白 (HSC70) 靶向肽组成。为了有效地将CMATAC递送至肿瘤细胞内，采用脂质纳米粒子（LNP）封装CMATAC（nCMATAC），并用胰岛素样生长因子2受体（IGF2R）靶向肽（InCMATAC）修饰，以实现肿瘤靶向和精确递送。模拟禁食饮食 (FMD) 可激活肿瘤细胞中的 CMA 通路。此外，FMD 治疗通过上调 IGF2R 表达，强烈增强 InCMATAC 的细胞摄取和肿瘤积累。因此，InCMATAC 可以有效降解 A549 和 HCC827 肿瘤细胞中的 STAT3 蛋白，并抑制体内肿瘤生长。这项研究表明 InCMATAC 可用于癌症治疗中的选择性蛋白水解。

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Targeted Degradation of Signal Transduction and Activator of Transcription 3 by Chaperone-Mediated Autophagy Targeting Chimeric Nanoplatform

Chaperone-mediated autophagy (CMA) is a lysosomal-dependent proteolysis pathway for the degradation of cytosolic proteins. However, exploiting CMA-mediated proteolysis to degrade proteins of interest in cancer therapy has not been widely applied. In this study, we develop a CMA-targeting chimera (CMATAC) to efficiently and specifically degrade signal transduction and activator of transcription 3 (STAT3) in tumor cells. CMATAC consists of STAT3 and heat shock cognate 70 kDa protein (HSC70) targeting peptides connected by a linker. To efficiently deliver CMATACs into tumor cells, lipid nanoparticles (LNPs) are used to encapsulate CMATACs (nCMATACs) and decorated with an insulin-like growth factor 2 receptor (IGF2R) targeting peptide (InCMATACs) to achieve tumor targeting and precise delivery. The CMA pathway is activated in tumor cells by a fasting-mimicking diet (FMD). Furthermore, FMD treatment strongly enhances the cellular uptake and tumor accumulation of InCMATACs by upregulating the IGF2R expression. As a result, InCMATACs efficiently degrade STAT3 protein in both A549 and HCC827 tumor cells and inhibit tumor growths in vivo. This study demonstrates that InCMATACs can be used for selective proteolysis in cancer therapy.

更新日期：2023-12-29

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