Submolecular modulation of PIEZO1 mechanotransduction with wireless tailor-made nanoswitches

PIEZO mechanoreceptors play critical roles in fundamental physiological processes such as proprioception or musculoskeletal biomechanics. However, their complex gating mechanisms and downstream signaling are still not completely understood, mainly due to the lack of effective probing tools. Here, we combine molecular imprinting and magnetic concepts to develop tailor-made nanoswitches enabling wireless targeted actuation of PIEZO1. Two epitopes selected in silico from distinct domains of PIEZO1 were used as templates for synthesizing magnetically responsive molecularly imprinted nanoparticles. These nanoswitches showed sub-nanomolar affinity for their respective epitope and recognized PIEZO1 in endothelial cells, similarly to antibodies. Applying magnetic fields to actuate PIEZO1 through nanoswitches led to increased calcium signaling, Yes-associated protein (YAP) nuclear translocation, and significant changes in the expression of genes related to PIEZO1 activity, implying that they can transduce the stimulus into intracellular signaling effects. Finally, this wireless actuation system proved to be effective in differentially modulating the behavior of mesenchymal stem cells. Remarkably, the selective targeting of each epitope led to contrasting downstream signaling cascades, implying distinct roles for each superstructure domain in the sophisticated function of these channels. Overall, this technology constitutes a promising tool for studying PIEZO-mediated mechanobiology, opening perspectives for harnessing its potential toward therapeutic approaches.