Photothermal Nanoswitches Enable Precision Modulation of Paradoxical Signaling Pathways for Targeted Therapy

ABSTRACT The regulation of signal transduction pathways presents a fundamental challenge in oncology due to their strong context dependence. While moderate pathway activity promotes tumor progression, excessive activation can be inhibitory—a balance that conventional approaches lack the spatiotemporal precision to control. To address this challenge, a photothermal nanoswitch composed of gold nanorods functionalized with the pathway‐specific protein complex of Wnt and its natural inhibitor Wif1 (Wnt inhibitory factor 1), has been developed to enable remote‐controlled signaling pathway modulation. Upon near‐infrared irradiation, photothermal heating induces complex dissociation, resulting in the localized release of signaling molecules. Combined with mild photothermal heating, this approach selectively amplifies pathway activity, exploiting the unique signaling landscape of malignant cells—characterized by altered receptor levels, β‐catenin stabilization, and impaired degradation pathways—to initiate apoptosis. Importantly, normal cells remain protected due to their intact regulatory mechanisms and higher activation thresholds. The modular design, allowing substitution of pathway‐specific components while retaining core photothermal control, extends this platform's application to diverse signaling networks, enabling selective modulation of pathways in cancer, immunity, and tissue homeostasis. By integrating spatial targeting, temporal control, and pathway‐specific amplification, this technology transforms the signaling paradoxes into precise therapeutic opportunities, paving the way for precision medicine.