A Nucleic Acid-Based LYTAC Plus Platform to Simultaneously Mediate Disease-Driven Protein Downregulation,Advanced Science

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A Nucleic Acid-Based LYTAC Plus Platform to Simultaneously Mediate Disease-Driven Protein Downregulation
Advanced Science ( IF 14.3 ) Pub Date : 2024-01-22 , DOI: 10.1002/advs.202306248
Yangyang Huang ₁ , Xujiao Zhou ₂ , Yirou Zhang ₂ , Miao Xie ₁ , Fujun Wang ₁ , Jingcan Qin ₃ , Han Ye ₂ , Hong Zhang _{2,

4} , Chuan Zhang ₁ , Jiaxu Hong _{2,

5}

Affiliation

Protein degradation techniques, such as proteolysis-targeting chimeras (PROTACs) and lysosome-targeting chimeras (LYTACs), have emerged as promising therapeutic strategies for the treatment of diseases. However, the efficacy of current protein degradation methods still needs to be improved to address the complex mechanisms underlying diseases. Herein, a LYTAC Plus hydrogel engineered is proposed by nucleic acid self-assembly, which integrates a gene silencing motif into a LYTAC construct to enhance its therapeutic potential. As a proof-of-concept study, vascular endothelial growth factor receptor (VEGFR)-binding peptides and mannose-6 phosphate (M6P) moieties into a self-assembled nucleic acid hydrogel are introduced, enabling its LYTAC capability. Small interference RNAs (siRNAs) is then employed that target the angiopoietin-2 (ANG-2) gene as cross-linkers for hydrogel formation, giving the final LYTAC Plus hydrogel gene silencing ability. With dual functionalities, the LYTAC Plus hydrogel demonstrated effectiveness in simultaneously reducing the levels of VEGFR-2 and ANG-2 both in vitro and in vivo, as well as in improving therapeutic outcomes in treating neovascular age-related macular degeneration in a mouse model. As a general material platform, the LYTAC Plus hydrogel may possess great potential for the treatment of various diseases and warrant further investigation.

中文翻译：

基于核酸的 LYTAC Plus 平台可同时介导疾病驱动的蛋白质下调

蛋白质降解技术，例如蛋白水解靶向嵌合体（PROTAC）和溶酶体靶向嵌合体（LYTAC），已成为治疗疾病的有前途的治疗策略。然而，当前蛋白质降解方法的功效仍需要提高，以解决疾病背后的复杂机制。在此，提出了通过核酸自组装设计的LYTAC Plus水凝胶，它将基因沉默基序整合到LYTAC构建体中以增强其治疗潜力。作为一项概念验证研究，将血管内皮生长因子受体 (VEGFR) 结合肽和 6 磷酸甘露糖 (M6P) 部分引入自组装核酸水凝胶中，使其具有 LYTAC 功能。然后使用小干扰 RNA (siRNA) 靶向血管生成素-2 (ANG-2) 基因作为水凝胶形成的交联剂，从而赋予最终的 LYTAC Plus 水凝胶基因沉默能力。 LYTAC Plus 水凝胶具有双重功能，在体外和体内同时降低 VEGFR-2 和 ANG-2 水平，以及改善小鼠模型中新生血管性年龄相关性黄斑变性的治疗效果。作为通用材料平台，LYTAC Plus水凝胶可能具有治疗各种疾病的巨大潜力，值得进一步研究。

更新日期：2024-01-22

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