Nano-LYTACs for Degradation of Membrane Proteins and Inhibition of CD24/Siglec-10 Signaling Pathway,Advanced Science

当前位置： X-MOL 学术 › Adv. Sci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Nano-LYTACs for Degradation of Membrane Proteins and Inhibition of CD24/Siglec-10 Signaling Pathway
Advanced Science ( IF 14.3 ) Pub Date : 2023-03-03 , DOI: 10.1002/advs.202300288
Kun Wang _{1,

2} , Albert Yu ₁ , Kewei Liu ₁ , Chunyan Feng ₁ , Yibo Hou ₁ , Jiawei Chen ₁ , Shaohua Ma ₁ , Laiqiang Huang _{1,

2} , Xiaoyong Dai ₁

Affiliation

Lysosome-targeting chimeras (LYTACs) are an emerging therapeutic modality that effectively degrade cancer cell membranes and extracellular target proteins. In this study, a nanosphere-based LYTAC degradation system is developed. The amphiphilic peptide-modified N-acetylgalactosamine (GalNAc) can self-assemble into nanospheres with a strong affinity for asialoglycoprotein receptor targets. They can degrade different membranes and extracellular proteins by linking with the relevant antibodies. CD24, a heavily glycosylated glycosylphosphatidylinositol-anchored surface protein, interacts with Siglec-10 to modulate the tumor immune response. The novel Nanosphere-AntiCD24, synthesized by linking nanospheres with CD24 antibody, accurately regulates the degradation of CD24 protein and partially restores the phagocytic function of macrophages toward tumor cells by blocking the CD24/Siglec-10 signaling pathway. When Nanosphere-AntiCD24 is combined with glucose oxidase, an enzyme promoting the oxidative decomposition of glucose, the combination not only effectively restores the function of macrophages in vitro but also suppresses tumor growth in xenograft mouse models without detectable toxicity to normal tissues. The results indicate that GalNAc-modified nanospheres, as a part of LYTACs, can be successfully internalized and are an effective drug-loading platform and a modular degradation strategy for the lysosomal degradation of cell membrane and extracellular proteins, which can be broadly applied in the fields of biochemistry and tumor therapeutics.

中文翻译：

用于膜蛋白降解和 CD24/Siglec-10 信号通路抑制的纳米 LYTAC

溶酶体靶向嵌合体（LYTAC）是一种新兴的治疗方式，可以有效降解癌细胞膜和细胞外靶蛋白。在这项研究中，开发了一种基于纳米球的 LYTAC 降解系统。两亲肽修饰的N-乙酰半乳糖胺 (GalNAc) 可以自组装成纳米球，对脱唾液酸糖蛋白受体靶标具有很强的亲和力。它们可以通过与相关抗体连接来降解不同的膜和细胞外蛋白。CD24 是一种高度糖基化的糖基磷脂酰肌醇锚定表面蛋白，与 Siglec-10 相互作用以调节肿瘤免疫反应。通过纳米球与CD24抗体连接合成的新型纳米球-AntiCD24，通过阻断CD24/Siglec-10信号通路，精确调控CD24蛋白的降解，并部分恢复巨噬细胞对肿瘤细胞的吞噬功能。当 Nanosphere-AntiCD24 与葡萄糖氧化酶（一种促进葡萄糖氧化分解的酶）结合时，该组合不仅可以有效恢复体外巨噬细胞的功能，而且可以抑制异种移植小鼠模型中的肿瘤生长，且对正常组织没有检测到毒性。结果表明，GalNAc修饰的纳米球作为LYTAC的一部分，可以成功内化，是一种有效的载药平台，也是细胞膜和细胞外蛋白溶酶体降解的模块化降解策略，可广泛应用于生物化学和肿瘤治疗领域。

更新日期：2023-03-03

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南