Programming DNA Nanoassemblies into Polyvalent Lysosomal Degraders for Potent Degradation of Pathogenic Membrane Proteins,Nano Letters

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Programming DNA Nanoassemblies into Polyvalent Lysosomal Degraders for Potent Degradation of Pathogenic Membrane Proteins
Nano Letters ( IF 9.6 ) Pub Date : 2024-09-03 , DOI: 10.1021/acs.nanolett.4c03102
Shuyi Yu ₁ , Tianhui Shi ₁ , Chenbiao Li ₁ , Chongyu Xie ₁ , Fuan Wang ₁ , Xiaoqing Liu _{1,

2}

Affiliation

Lysosome-targeting chimera (LYTAC) shows great promise for protein-based therapeutics by targeted degradation of disease-associated membrane or extracellular proteins, yet its efficiency is constrained by the limited binding affinity between LYTAC reagents and designated proteins. Here, we established a programmable and multivalent LYTAC system by tandem assembly of DNA into a high-affinity protein degrader, a heterodimer aptamer nanostructure targeting both pathogenic membrane protein and lysosome-targeting receptor (insulin-like growth factor 2 receptor, IGF2R) with adjustable spatial distribution or organization pattern. The DNA-based multivalent LYTACs showed enhanced efficacy in removing immune-checkpoint protein programmable death-ligand 1 (PD-L1) and vascular endothelial growth factor receptor 2 (VEGFR2) in tumor cell membrane that respectively motivated a significant increase in T cell activity and a potent effect on cancer cell growth inhibition. With high programmability and versatility, this multivalent LYTAC system holds considerable promise for realizing protein therapeutics with enhanced activity.

中文翻译：

将 DNA 纳米组装体编程为多价溶酶体降解剂，以有效降解致病膜蛋白

溶酶体靶向嵌合体 (LYTAC) 通过靶向降解与疾病相关的膜或细胞外蛋白，在基于蛋白质的治疗方面显示出巨大的前景，但其效率受到 LYTAC 试剂和指定蛋白质之间有限的结合亲和力的限制。在这里，我们通过将 DNA 串联组装成高亲和力蛋白质降解剂，建立了一个可编程的多价 LYTAC 系统，这是一种针对致病性膜蛋白和溶酶体靶向受体（胰岛素样生长因子 2 受体，IGF2R）的异二聚体适体纳米结构，具有可调节的空间分布或组织模式。基于 DNA 的多价 LYTAC 在去除肿瘤细胞膜中的免疫检查点蛋白可编程死亡配体 1 (PD-L1) 和血管内皮生长因子受体 2 (VEGFR2) 方面表现出增强的功效，这分别促进了 T 细胞活性的显着增加和对抑制癌细胞生长具有有效作用。这种多价 LYTAC 系统具有高度的可编程性和多功能性，对于实现具有增强活性的蛋白质疗法具有广阔的前景。

更新日期：2024-09-03

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