Cell material state determines high-frequency cell deformation and microbubble-induced permeabilization

Mechanical properties influence how cells withstand and transmit force, but their role in clinically relevant, high-frequency therapeutic perturbations remains poorly understood. Ultrasound-stimulated microbubbles can locally deform cells and tissues to enhance drug delivery, yet therapeutic responses vary markedly across mechanical microenvironments. How cellular material properties govern microbubble-cell interactions at megahertz loading rates - well beyond the range accessible to conventional mechanobiology - remains unresolved. Here we combine ultra-high-speed imaging with digital image correlation to map microbubble-induced deformation in living cells at ultrasound frequencies. We show that oscillating microbubbles generate harmonic deformation waves whose spatial decay defines a micrometre-scale attenuation length governed by cytoskeletal organisation and intracellular viscoelastic dissipation. Pharmacological softening or stiffening alters both deformation propagation and wave speed, and these mechanical changes predict permeabilisation efficiency in tumour-derived and primary human bone-marrow stromal cells. These findings establish cellular viscoelasticity as a determinant of microbubble bioeffects and suggest that tissue mechanical state can be used as a design parameter for ultrasound-mediated therapeutic delivery.