A Photothermal Nano‐Switch for Tumor‐Selective Wnt Hyperactivation in Vivo

Wnt signaling plays a paradoxical role in cancer, functioning as both a promoter and suppressor depending on its activation level. This duality underscores the critical need for precise and selective modulation, while existing Wnt-targeting strategies fail to achieve it due to inadequate specificity and control. Here, we report a photothermal nano-switch based on Wnt inhibitory factor-1 (Wif1) and Wnt-functionalized gold nanorods (Au-PEG/Wif1/Wnt) that enables spatiotemporal and selective activation of the Wnt pathway. Upon near-infrared light irradiation, localized heating disrupts Wif1-Wnt interactions, triggering controlled Wnt protein release. The liberated Wnt ligands, combined with mild photothermal heating, hyperactivate the Wnt pathway specifically by inhibiting the phosphorylation of β-catenin in tumor cells, thus inducing epithelial-mesenchymal transition, β-catenin nuclear translocation, and apoptosis. In contrast, normal cells remain unaffected due to their lower basal Wnt activity, as confirmed by negligible cytotoxicity and unaltered apoptotic markers. In vivo, this system achieves robust antitumor effects in a 4T1 breast cancer model while ensuring safety for healthy tissues. By leveraging the optical properties of gold nanorods for conditional and selective activation, this study establishes a transformative platform for the precise modulation of Wnt signaling, offering significant promise for treating Wnt-dysregulated diseases with minimal off-target effects.