DNA Framework-Based Lysosome-Targeting Chimeras: Intracellular ATP-Facilitated Extracellular Protein Degradation.

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.