Programmable DNA Nanospheres for Photothermal‐Controlled Intracellular Protein Degradation

Abstract Photothermal‐controlled protein degradation has recently emerged as a promising ubiquitin proteasome‐independent strategy for intracellular protein elimination by inducing localized heating to destroy target protein structures. However, current photothermal systems often suffer from low bioavailability and nonspecific distribution, which severely limit their therapeutic efficacy. Here, we report a programmable, photothermal‐responsive DNA nanosphere (NS) for targeted and spatiotemporally controlled intracellular protein degradation. The modular NS integrates a tumor‐targeting aptamer, a glutathione (GSH)‐responsive disulfide linker, and a degradation unit composed of a photosensitizer and a protein‐binding aptamer. After selective accumulation in tumor cells, the NS disassembles in the GSH‐rich cytoplasm, releasing degradation modules that bind target proteins. Subsequent laser irradiation induces localized heating to disrupt protein conformation and activate autophagy–lysosomal clearance. This strategy enabled efficient programmed death‐ligand 1 (PD‐L1) degradation across multiple cancer cell models and demonstrated adaptability to other targets such as vascular endothelial growth factor (VEGF), thereby achieving synergistic antitumor effects with mild phototherapy. With improved tumor selectivity, cellular permeability, in vivo stability, and a highly modular design, this platform offers a multifunctional and translatable solution for intracellular protein degradation–based cancer therapy.