A Cascade-Targeted Enzyme-Instructed Peptide Self-Assembly Strategy for Cancer Immunotherapy through Boosting Immunogenic Cell Death,Small Methods

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A Cascade-Targeted Enzyme-Instructed Peptide Self-Assembly Strategy for Cancer Immunotherapy through Boosting Immunogenic Cell Death
Small Methods ( IF 10.7 ) Pub Date : 2023-03-25 , DOI: 10.1002/smtd.202201416
Limin Xie _{1,

2} , Yinghao Ding ₂ , Xiangyang Zhang ₂ , Zhenghao Zhang ₂ , Sheng Zeng _{3,

4} , Ling Wang ₁ , Zhimou Yang ₂ , Qian Liu _{3,

4} , Zhi-Wen Hu ₂

Affiliation

Immunogenic cell death (ICD) approaches by encumbering mitochondrial functions provide great promise for the treatment of malignant tumors, but these kinds of ICD strategies are still in their infancy. Here, one multifunctional drug-loaded, cascade-targeted, and enzyme-instructed self-assembling peptide nanomedicine (Comp. 4) for ICD-based cancer therapy is constructed. Comp. 4 consists of 1) lonidamine (LND) that specifically interferes with mitochondrial functions; 2) a programmed death ligand 1 (PD-L1) binding peptide sequence (NTYYEDQG) and a mitochondria-specific motif (triphenylphosphonium, TPP) that can sequentially control the cell membrane and mitochondria targeting capacities, respectively; and 3) a -G^DF^DFp^DY- assembly core to in situ organize peptide assemblies responsive to alkaline phosphatase (ALP). Comp. 4 demonstrates noticeable structural and morphological transformations in the presence of ALP and produces peptide assemblies in mouse colon cancer cells (CT26) with high expressions of both ALP and PD-L1. Moreover, the presence of PD-L1- and mitochondria-specific motifs can assist Comp. 4 for effective endocytosis and endosomal escape, forming peptide assemblies and delivering LND into mitochondria. Consequently, Comp. 4 shows superior capacities to in vivo induce abundant mitochondrial oxidative stress, provoke robust ICD responses, and produce an immunogenic tumor microenvironment, successfully inhibiting CT26 tumor growth by eliciting a systemic ICD-based antitumor immunity.

中文翻译：

通过促进免疫原性细胞死亡进行癌症免疫治疗的级联靶向酶指导肽自组装策略

通过阻碍线粒体功能的免疫原性细胞死亡 (ICD) 方法为恶性肿瘤的治疗提供了巨大希望，但这些类型的 ICD 策略仍处于起步阶段。在这里，构建了一种用于基于 ICD 的癌症治疗的多功能载药、级联靶向和酶指导的自组装肽纳米药物 ( Comp. 4 )。比较。4包括 1) 专门干扰线粒体功能的洛尼达明 (LND)；2) 程序性死亡配体 1 (PD-L1) 结合肽序列 (NTYYEDQG) 和线粒体特异性基序 (triphenylphosphonium, TPP)，分别可以依次控制细胞膜和线粒体靶向能力；和 3) a -G ^D F ^D Fp ^DY-组装核心原位组织响应碱性磷酸酶 (ALP) 的肽组装。比较。图 4展示了在存在 ALP 的情况下显着的结构和形态转变，并在 ALP 和 PD-L1 均高表达的小鼠结肠癌细胞 (CT26) 中产生肽组装。此外，PD-L1 和线粒体特异性基序的存在可以帮助Comp。4用于有效的内吞作用和内体逃逸，形成肽组装并将 LND 输送到线粒体中。因此，比较。4个显示出在体内诱导丰富的线粒体氧化应激、激发强烈的 ICD 反应和产生免疫原性肿瘤微环境的卓越能力，通过引发系统的基于 ICD 的抗肿瘤免疫成功抑制 CT26 肿瘤生长。

更新日期：2023-03-25

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