Zhang Rongjun, Yang Changjie, Gao Xiaobo, He Zhenyang, Ji Ding-Kun, Tan Weihong
Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China.
Department of Laboratory Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310022, China.
J Am Chem Soc. 2025 Jun 18;147(24):20989-21002. doi: 10.1021/jacs.5c05456. Epub 2025 Jun 6.
Regulating membrane protein abundance through Lysosome Targeting Chimera (LYTAC) holds significant promise in addressing various diseases. However, the precise structural control of LYTAC molecules and how to improve their treatment efficacy remain elusive. In this study, we develop a multifunctional phototriggered LYTAC platform, named PT-LYTAC, to enhance targeted protein degradation using a photoactive bispecific aptamer chimera (PBAC). PBAC is designed with a precise modular approach that integrates an NIR photosensitive molecule into a bispecific aptamer chimera. Taking advantage of the low molecular weight and easy synthesis of the DNA aptamers, PBAC can efficiently transport the therapeutically relevant membrane protein PTK7 to lysosomes for degradation through the lysosomal pathway. Moreover, our investigation reveals that the multifunctional PT-LYTAC platform, enabled by DNA aptamers, promotes protein degradation by modulating cellular autophagy. By the combination of targeted protein degradation and spatiotemporally controllable regulation of intracellular oxidative stress, the function of tumor cells can be significantly inhibited. Under NIR laser irradiation, PT-LYTAC completely suppresses colorectal cancer growth with just one dose and a single laser treatment, all without any apparent side effects. We anticipate that this novel PT-LYTAC will expand the use of DNA-based LYTAC drugs and provide a new dimension for targeted protein degradation.
通过溶酶体靶向嵌合体（LYTAC）调节膜蛋白丰度在治疗各种疾病方面具有重大前景。然而，LYTAC分子的精确结构控制以及如何提高其治疗效果仍然不清楚。在本研究中，我们开发了一种多功能光触发LYTAC平台，名为PT-LYTAC，以利用光活性双特异性适配体嵌合体（PBAC）增强靶向蛋白降解。PBAC采用精确的模块化方法设计，将近红外光敏分子整合到双特异性适配体嵌合体中。利用DNA适配体分子量低且易于合成的特点，PBAC可以通过溶酶体途径有效地将与治疗相关的膜蛋白PTK7转运到溶酶体进行降解。此外，我们的研究表明，由DNA适配体实现的多功能PT-LYTAC平台通过调节细胞自噬促进蛋白降解。通过靶向蛋白降解和细胞内氧化应激的时空可控调节相结合，可以显著抑制肿瘤细胞的功能。在近红外激光照射下，PT-LYTAC只需一剂和一次激光治疗就能完全抑制结直肠癌的生长，且无任何明显副作用。我们预计这种新型PT-LYTAC将扩大基于DNA的LYTAC药物的应用，并为靶向蛋白降解提供新的维度。
