MechanoMR microparticle (M3) sensors reveal dynamic stress loading as a driver of epithelial-mesenchymal transition

Abstract

The dynamic mechanical response of tissues underlies their physiological function, yet direct, quantitative measurement of tissue stress in vivo has remained a major challenge. Here, we introduce the mechanoMR microparticle (M3, "M-cube") sensor, a hybrid soft-matter/nanoparticle probe that integrates directly into tissue mechanical networks while transducing local stress into quantitative magnetic resonance (MR) readouts with single-particle resolution. We demonstrate the utility of this platform across diverse model systems, including tumor spheroids, Xenopus embryos, and mouse xenografts, where the M3 sensor enables noninvasive, spatiotemporally resolved mapping of tissue stress dynamics during cancer development. Using this approach, we reveal that epithelial-mesenchymal transition (EMT) is accompanied by distinctive stress-remodeling patterns observable in vivo. Strikingly, we find that abrupt stress increases, rather than cumulative or peak stress magnitude, are the key determinants of EMT induction in cancer cells within the tumor microenvironment. Transcriptomic profiling under controlled stress-loading dynamics shows that sustained yet gradual stress escalation activates cytoprotective antioxidation pathways (e.g., FOXO/AMPK) that reinforce epithelial stability, whereas acute stress surges overwhelm these defense mechanisms, predisposing cells toward mesenchymal reprogramming. These findings establish the M3 sensor as a broadly applicable technology for linking dynamic mechanical cues to cell-state transitions in development, homeostasis, and disease.