Logic Gate Activated Lysosome Targeting DNA Nanodevice for Controlled Proteins Degradation

Abstract Targeted protein degradation (TPD) is a powerful technique for the regulation of protein homeostasis. Current TPD mainly focuses on the therapeutical consequences rather than the operation processes of the molecular tools. Herein, a platform for precise manipulation of the protein degradation by activatable lysosome targeting DNA nanodevices is constructed. In the design, a lysosome‐targeting CD63 aptamer is locked by the single‐stranded DNA with a photocleavable group and a disulfide bond. This locked CD63 aptamer is connected with the aptamer targeting the protein of interest via double‐stranded DNA linkages to form the logic‐gate activated lysosome targeting DNA nanodevice (LALTD). With the UV light and endogenous GSH as inputs, an AND logic gate is built to efficiently manipulate the protein delivery processes by LALTD. The protein of interest can be degraded via efficient lysosome hydrolysis. Further studies show that the logic‐gate operation can be used for modulating T cell‐mediated antitumor immunity. The modularly designed activatable lysosome targeting DNA nanodevices exhibits good stability, controllability, programmability, and universality, providing a new prospect for accurate protein degradation and precise therapy.