A magnetogenetic atlas of cytoskeleton-resolved gene regulation in mesenchymal stem cells

Mechanical force is a universal language of cells, yet which transcripts report tension on individual cytoskeletal polymers has remained unknown. Existing stretchers and drugs distort every filament simultaneously, blurring the signal. Here we apply a magnetogenetic approach, using antibody-guided 10 nm Fe 3 O 4 nanoparticles to exert ∼0.5 pN force on β-actin, α-tubulin, or vimentin in human mesenchymal stem cells, and record the 20-h transcriptional response by bulk RNA-seq. Tension on microtubules amplifies Wnt, focal-adhesion, and extracellular-matrix modules; vimentin loading activates Hippo signalling, DNA-replication, and cell-cycle engines; actin loading elicits a TGF-β-centred oxidative-stress and ferroptosis programme, revealing a striking division of labour among the three polymers. Only four genes: KLHL24, RGS4, FMN2, and PDE4DIP are shared across the 384–405 differentially expressed transcripts per condition, exposing an orthogonal “filament code” for mechanosensation. The data overturn the view that the cytoskeleton transmits force through common pathways and identify a minimal, four-gene set that reports intracellular tension regardless of where it is applied. Because magnetic fields penetrate tissue centimetres deep and can be shaped in space and time, this platform offers a non-invasive route to steer stem-cell migration (via tubulin), proliferation (via vimentin), or cytoprotection (via actin), informing the design of mechano-responsive biomaterials and remotely controllable cell therapies. Statement of significance Cells sense mechanical forces, but standard stretch devices and drugs activate the whole cytoskeleton at once, making it hard to isolate each filament’s role. We used antibody-guided 10 nm Fe 3 O 4 nanoparticles to apply ∼0.5 pN tension specifically to actin, microtubules, or vimentin in mesenchymal stem cells, then read out the 20 h response by RNA sequencing. Each filament triggers a largely distinct gene program, with only four shared genes, revealing a simple filament code for force signaling. This resolves a long-standing assignment problem and provides testable markers of intracellular tension. Because magnetic fields penetrate tissue and are easily shaped, our strategy suggests non-invasive ways to guide migration, proliferation, or cytoprotection, informing mechano-responsive biomaterials and remotely controllable cell therapies.