Photoactivatable DNA Conveyer Ferries Cellular Receptors to Lysosome for Collaborative Degradation in Zebrafish

Targeted protein degradation (TPD) offers significant potential for modulating disease-driving receptor functions in vivo as an antitumor strategy. However, mitigating off-target effects and enhancing therapeutic efficacy within the complex tumor microenvironment remain critical challenges. Herein, we introduce a photoactivatable DNA conveyer (PhoDC) designed for the collaborative degradation of two functionally linked receptors with high spatiotemporal resolution in vivo. This strategy utilizes an exogenous light signal to trigger a conformational switch in the DNA conveyer. Upon activation, PhoDC captures and ferries the dual-targeted receptors from the cell membrane to the lysosome for simultaneous degradation. This approach effectively achieved concurrent downregulation of the target receptors and suppressed tumor growth in a zebrafish xenograft model with precise controllability. By leveraging modular and versatile aptameric nucleic acids, the PhoDC platform offers improved safety and efficacy for cellular receptor degradation while circumventing complicated synthesis procedures. Therefore, this photoactivatable DNA conveyer holds considerable promise for advancing the development of precision cancer therapies.