Ning Yujun, Li Bin, Chen Weishuai, Feng Langxia, Huang Xuedong, Liu Baohong
Department of Chemistry, Shanghai Stomatological Hospital, State Key Laboratory of Molecular Engineering of Polymers and Institute of Biomedical Sciences, Fudan University, Shanghai 200433, People's Republic of China.
ACS Nano. 2025 Apr 29;19(16):15853-15862. doi: 10.1021/acsnano.5c00745. Epub 2025 Apr 16.
Targeted protein degradation (TPD) offered a riveting therapeutic paradigm to eradicate pathogenesis-relevant proteins, especially those belonging to the once-considered undruggable proteome. Considering that adenosine triphosphate (ATP) is the primary energy source for cell activities and lysosomes are important ATP storage sites, herein, the first example of dual-function tetrahedral DNA framework-based lysosome-targeting chimeras (TDF-LYTACs) is proposed for elucidating the correlation between extracellular protein degradation via the lysosome pathway and the fluctuations in intracellular ATP levels. In our study, platelet-derived growth factor (PDGF), a driver of cancer invasion and metastasis, was chosen as the protein of interest. To achieve multifunctionality, we employed a tetrahedral DNA framework formed by an aptamer of PDGF, human apurinic/apyrimidinic endonuclease 1 (APE1)-triggered ATP probes, and a ligand of the cell-surface lysosome-shuttling receptor (IGFIIR). TDF-LYTACs efficiently and quickly shuttled PDGF proteins to lysosomes, degraded them through the lysosomal pathway, and further visualized the intracellular ATP level synchronously. Furthermore, we found a significant correlation between the degradation efficiency of PDGF and intracellular ATP levels over time; that is, a higher ATP level corresponded to higher degradation efficiency and vice versa. We anticipate that our versatile TDF-LYTACs will offer a perspective for degrading multifunctional extracellular proteins.
靶向蛋白质降解（TPD）为根除与发病机制相关的蛋白质提供了一种引人注目的治疗模式，尤其是那些属于曾经被认为不可成药的蛋白质组的蛋白质。考虑到三磷酸腺苷（ATP）是细胞活动的主要能量来源，且溶酶体是重要的ATP储存位点，在此，我们提出了首个基于双功能四面体DNA框架的溶酶体靶向嵌合体（TDF-LYTACs）实例，以阐明通过溶酶体途径进行的细胞外蛋白质降解与细胞内ATP水平波动之间的相关性。在我们的研究中，选择了血小板衍生生长因子（PDGF），一种癌症侵袭和转移的驱动因子，作为目标蛋白质。为实现多功能性，我们采用了由PDGF适配体、人脱嘌呤/脱嘧啶内切核酸酶1（APE1）触发的ATP探针以及细胞表面溶酶体穿梭受体（IGFIIR）的配体形成的四面体DNA框架。TDF-LYTACs高效且快速地将PDGF蛋白转运至溶酶体，通过溶酶体途径将其降解，并进一步同步可视化细胞内ATP水平。此外，我们发现随着时间的推移，PDGF的降解效率与细胞内ATP水平之间存在显著相关性；也就是说，较高的ATP水平对应较高的降解效率，反之亦然。我们预计，我们多功能的TDF-LYTACs将为降解多功能细胞外蛋白质提供一个新视角。
