Visualizing nuclear mechanotransduction with FRET-based biosensors

Cells continuously sense and respond to mechanical cues from their microenvironment, converting physical stimuli into biochemical signals that regulate gene expression and cellular behavior. This review focuses on the structural and molecular basis of nuclear mechanotransduction and highlights recent advances in fluorescence resonance energy transfer (FRET)-based biosensors developed to interrogate these processes in living cells. We conceptualize nuclear mechanotransduction as three interconnected pillars: (i) direct force transmission through the LINC complex, (ii) structural mechanosensing mediated by nuclear deformation involving the nuclear lamina and nuclear pore complex, and (iii) transcriptional mechanotransduction driven by epigenetic regulation and mechanosensitive signaling pathways. Because mechanical signals are rapid, spatially localized, and highly dynamic, FRET has emerged as a powerful approach for real-time visualization of nuclear mechanics. Its sensitivity to nanoscale distance and molecular orientation enables detection of force-induced protein rearrangements and dynamic structural transitions within the nucleus. Accordingly, we review recent FRET-based strategies for probing force transmission at the nuclear envelope, lamina strain, and LEM-domain/BAF protein dynamics, as well as biosensors reporting mechanically regulated histone modifications and YAP nuclear localization. Together, this review provides a unified framework for understanding nuclear mechanotransduction and underscores the expanding role of FRET-based tools in dissecting nuclear mechanics with high spatiotemporal resolution.