A Photothermal Nano-Switch for Tumor-Selective Wnt Hyperactivation in Vivo
Chunyan Fang1, Yamin Liu1, Bo Zhang1
1Frontiers 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.
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.
Insights
This study introduces a novel photothermal nano-switch for precise Wnt pathway control in cancer. The device selectively targets tumors, activating Wnt signaling to induce cancer cell death while sparing healthy tissues.
Area of Science:
- Biomedical Engineering
- Cancer Biology
- Nanotechnology
Background:
- Wnt signaling has a dual role in cancer, acting as both a promoter and suppressor.
- Current Wnt-targeting strategies lack specificity and control.
- Precise modulation of Wnt signaling is crucial for effective cancer therapy.
Purpose of the Study:
- To develop a photothermal nano-switch for spatiotemporal and selective Wnt pathway activation.
- To investigate the therapeutic potential of this nano-switch in a breast cancer model.
- To demonstrate the safety and efficacy of targeted Wnt pathway modulation.
Main Methods:
- Fabrication of a nano-switch using Wnt inhibitory factor-1 (Wif1) and Wnt-functionalized gold nanorods (Au-PEG/Wif1/Wnt).
- Utilized near-infrared light irradiation for localized heating and controlled Wnt protein release.
- Assessed Wnt pathway activation, including β-catenin phosphorylation, nuclear translocation, and apoptosis induction in tumor and normal cells.
- Evaluated in vivo antitumor efficacy and safety in a 4T1 breast cancer mouse model.
Main Results:
- The nano-switch enabled spatiotemporal Wnt pathway activation upon near-infrared irradiation.
- Selective hyperactivation of Wnt signaling in tumor cells led to epithelial-mesenchymal transition, β-catenin nuclear translocation, and apoptosis.
- Normal cells showed negligible cytotoxicity and unaltered apoptotic markers, indicating high selectivity.
- Significant in vivo antitumor effects were observed in the 4T1 breast cancer model with minimal impact on healthy tissues.
Conclusions:
- The photothermal nano-switch provides precise and selective control over Wnt signaling.
- This technology offers a promising platform for treating Wnt-dysregulated diseases with reduced off-target effects.
- The study highlights the potential of nanotechnology in developing targeted cancer therapies.
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