高等学校化学学报

高等学校化学学报

• 研究论文 • 上一篇    下一篇

基于高内吞效率的核酸适体构建LYTAC嵌合体以增强白血病细胞膜蛋白的降解

陈卓然,龚玲玉,艾立丽,张鹏,周艳华   

  1. 贵州医科大学组织工程与干细胞实验中心，贵州生物制造实验室，功能核酸生物药研究重点实验室
  • 收稿日期:2026-01-08 修回日期:2026-03-23 网络首发:2026-03-25 发布日期:2026-03-25
  • 通讯作者: 周艳华 E-mail:zhouyanhua@gmc.edu.cn
  • 基金资助:
    国家自然科学基金(批准号: 81960036, 22564008)、贵州省教育厅高校科技创新团队(批准号：黔教计[2023]068)和贵州省卫生健康委科学技术基金项目(批准号: gzwkj2021-157, 2024GZWJKJXM0466)资助

A High-Internalization-Efficiency Aptamer-Based LYTAC Chimera for Enhanced Degradation of Leukemia Cell Membrane Proteins

CHEN Zhuoran, GONG Linyu, AI Lili, ZHANG Peng, ZHOU Yanhua   

  1. Center for Tissue Engineering and Stem Cell Research, Guizhou Biomanufacturing Laboratory, Key Laboratory of Functional Nucleic Acids-Based Biopharmaceutical Research, Guizhou Medical University
  • Received:2026-01-08 Revised:2026-03-23 Online First:2026-03-25 Published:2026-03-25
  • Supported by:
    Supported by the National Natural Science Foundation of China(Nos.81960036, 22564008), the Higher Education Institutions Scientific and Technological Innovation Team of Guizhou Province(No.qianjiaoji2023-068) and the Scientific and Technological Fund Program of Guizhou Provincial Health Commission(Nos. gzwkj2021-157, 2024GZWJKJXM0466)

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摘要： 急性髓系白血病（AML）是一类恶性血液肿瘤，现有疗法仍面临着复发率高与副作用大等挑战，亟待开发新型的治疗策略。转铁蛋白受体（transferrin receptor 1, TfR1/CD71）是调控细胞铁代谢与增殖的关键蛋白，其在AML等白血病细胞表面高表达，成为颇具潜力的治疗靶点。本研究基于溶酶体靶向嵌合体（LYTACs）技术，以具有高内吞效率的CD71靶向核酸适体HG9作为识别模块，通过共价连接溶酶体导向配体三乙酰半乳糖胺（triGalNAc），设计并合成了一种新型双功能嵌合分子HG910tri，旨在实现CD71的高效、特异性降解。研究结果表明，该嵌合分子可有效识别AML细胞系，并通过去唾液酸糖蛋白受体（ASGPR）介导的内吞溶酶体途径显著下调细胞表面CD71蛋白表达水平，降解作用呈现明显的时间和浓度依赖性。而且，CD71降解能够有效抑制AML细胞系MV4-11的细胞活力，并进一步诱导细胞凋亡与G1期周期阻滞。本工作构建了一种基于高内吞核酸适体的高效LYTACs分子，其能高效降解CD71，并能有效抑制MV4-11细胞增殖，为治疗CD71高表达的急性髓系白血病提供了新策略。

关键词: CD71, 细胞膜降解, LYTACs, 核酸适体, 三乙酰半乳糖胺

Abstract: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with limited treatment options due to high relapse rates and severe side effects, highlighting the demand for innovative therapeutic approaches. The transferrin receptor 1 (TfR1/CD71), a critical regulator of cellular iron uptake and proliferation, is markedly overexpressed on AML and other leukemia cells, rendering it an attractive therapeutic target. Leveraging lysosome-targeting chimera (LYTAC) technology, we designed and synthesized a novel bifunctional molecule, HG9-10-tri, composed of a high-internalizing CD71-targeting aptamer (HG9) conjugated to the lysosome-directing ligand triacetyl galactosamine (triGalNAc). This chimera enables efficient and specific degradation of CD71 via the asialoglycoprotein receptor (ASGPR)-mediated endolysosomal pathway.

Key words: CD71; Cell membrane degradation, LYTACs, Aptamer, tri-GalNAc (Triacetylgalactosamine)

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