Peptide-Driven Proton Sponge Nano-Assembly for Imaging and Triggering Lysosome-Regulated Immunogenic Cancer Cell Death.
Peptide-Driven Proton Sponge Nano-Assembly for Imaging and Triggering Lysosome-Regulated Immunogenic Cancer Cell Death.
复制标题
肽驱动的质子海绵纳米组件用于成像和触发溶酶体调节的免疫原性癌细胞死亡。
DOI：
10.1002/adma.202307679
复制
发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Jokerst,JesseV
中科院分区：
文献类型：
--
作者：
He,Tengyu;Wen,Jing;Wang,Wenjian;Hu,Zeliang;Ling,Chuxuan;Zhao,Zhongchao;Cheng,Yong;Chang,Yu-Ci;Xu,Ming;Jin,Zhicheng;Amer,Lubna;Sasi,Lekshmi;Fu,Lei;Steinmetz,NicoleF;Rana,TariqM;Wu,Peng;Jokerst,JesseV
用纳米药物触发溶酶体调节的免疫原性细胞死亡(如下睑下垂和坏死性下垂)是一种新的方法，可以使“免疫冷”肿瘤变得“热”--这是癌症免疫治疗面临的一个关键挑战。质子海绵如高相对分子质量的支化聚乙烯亚胺(PEI)是一种很好的裂解溶酶体的材料，但由于其固定的电荷密度和对细胞死亡机制的不了解，其治疗应用受到无法控制的毒性的阻碍。在这里，一系列具有自组装、表面电荷密度和细胞毒性可控的质子海绵纳米组装(PSNAs)被创造出来。这类PSNA是通过低分子量支化PEI共价结合到携带四苯基乙烯吡啶(PYTPE，一种聚集诱导发光的发光体)的自组装肽上构建的。聚乙二醇单甲氧基异丙基异氰酸酯在聚乙二醇胺自组装肽的辅助下组装后，表面正电荷增强，细胞毒作用增强。通过调节多肽中的亲水和疏水成分，进一步优化了多糖核酸的自组装倾向，从而使多糖核酸具有最高的荧光、表面正电荷密度、细胞摄取和癌细胞毒性。系统的细胞死亡机制研究表明，溶酶体断裂调节的下垂和坏死性下垂至少是细胞死亡的两个原因。肿瘤细胞经历PSNA触发的ICD激活免疫细胞，表明PSNAs具有触发抗癌免疫的巨大潜力。
Triggering lysosome‐regulated immunogenic cell death (ICD, e.g., pyroptosis and necroptosis) with nanomedicines is an emerging approach for turning an “immune‐cold” tumor “hot”—a key challenge faced by cancer immunotherapies. Proton sponge such as high‐molecular‐weight branched polyethylenimine (PEI) is excellent at rupturing lysosomes, but its therapeutic application is hindered by uncontrollable toxicity due to fixed charge density and poor understanding of resulted cell death mechanism. Here, a series of proton sponge nano‐assemblies (PSNAs) with self‐assembly controllable surface charge density and cell cytotoxicity are created. Such PSNAs are constructed via low‐molecular‐weight branched PEI covalently bound to self‐assembling peptides carrying tetraphenylethene pyridinium (PyTPE, an aggregation‐induced emission‐based luminogen). Assembly of PEI assisted by the self‐assembling peptide‐PyTPE leads to enhanced surface positive charges and cell cytotoxicity of PSNA. The self‐assembly tendency of PSNAs is further optimized by tuning hydrophilic and hydrophobic components within the peptide, thus resulting in the PSNA with the highest fluorescence, positive surface charge density, cell uptake, and cancer cell cytotoxicity. Systematic cell death mechanistic studies reveal that the lysosome rupturing‐regulated pyroptosis and necroptosis are at least two causes of cell death. Tumor cells undergoing PSNA‐triggered ICD activate immune cells, suggesting the great potential of PSNAs to trigger anticancer immunity.