A Photothermal Nano‐Switch for Tumor‐Selective Wnt Hyperactivation in Vivo
Abstract
Abstract 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.
Article Details
Authors (12)
Chunyan Fang
Frontiers Science Center for Transformative Molecules School of Chemistry and Chemical Engineering School of Biomedical Engineering National Center for Translational Medicine National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy Shanghai Jiao Tong University Shanghai 200240 P.R. China
Yamin Liu
Department of Biomedical Engineering, University of Connecticut Health
Bo Zhang
Tianqi Liu
School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University
Xi Hu
Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University
Bowen Li
Department of Chemistry, College of Arts and Sciences
Yuehao Gan
Frontiers Science Center for Transformative Molecules School of Chemistry and Chemical Engineering School of Biomedical Engineering National Center for Translational Medicine National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy Shanghai Jiao Tong University Shanghai 200240 P.R. China
Canyu Huang
Frontiers Science Center for Transformative Molecules School of Chemistry and Chemical Engineering School of Biomedical Engineering National Center for Translational Medicine National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy Shanghai Jiao Tong University Shanghai 200240 P.R. China
Pengpeng Xue
College of Pharmaceutical Sciences Zhejiang University Wuhu 241002 P.R. China
Shuyu Zhang
Fangyuan Li
Department of Clinical Laboratory, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders
Daishun Ling
State Key Laboratory of Synergistic Chem-Bio Synthesis, Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, School of Biomedical Engineering, National Engineering Research Center of Advanced Magnetic Resonance Technologies for Diagnosis and Therapy (NERC-AMRT), National Center for Translational Medicine