Remote Activation of Wnt Signaling and Cell Proliferation by E‐Cadherin Magnetomechanical Stimulation

ABSTRACT The ability to remotely and precisely manipulate intracellular signaling pathways is crucial for fundamental research and therapeutics. The Wnt/β‐catenin cascade regulates cell proliferation, differentiation, and tissue regeneration, but current pharmacological activation methods lack spatiotemporal control and induce off‐target effects. Here, we introduce a pioneering magnetogenetic toolkit to modulate the Wnt/β‐catenin pathway through magnetomechanical stimulation of E‐cadherin, a key cell adhesion molecule intimately linked to β‐catenin dynamics. Magnetic nanoparticles functionalized with the extracellular domain of E‐cadherin (MNPs@E/EC15) selectively bind cellular E‐cadherins. Applying a low‐intensity, low‐gradient magnetic field via a custom stimulator generates localized mechanical forces that trigger E‐cadherin mechanotransduction. This stimulation induces β‐catenin membrane release, nuclear translocation, and Wnt target gene activation, confirmed by transcriptomic profiling and a luciferase reporter assay. These molecular changes translate into enhanced cell proliferation and accelerated gap closure. This work establishes an innovative, non‐invasive tool for probing E‐cadherin mechanobiology and remotely modulating Wnt/β‐catenin signaling. Unlike other mechanotransduction tools, this approach enables simultaneous, high‐spatiotemporal modulation of multiple cells using low‐intensity magnetic fields adaptable for in vivo designs. Our findings open promising avenues for studying mechanotransduction and developing targeted regenerative therapies based on mechanical stimulation.