Mechanotherapy enhances nanodrug uptake by overcoming the actin cytoskeleton damping effect.

Efficient nanodrug therapy in solid tumors is limited not only by extracellular barriers but also by the mechanical state of the plasma membrane (PM). Although mechanotherapy remodels the extracellular matrix (ECM) and improves tissue-level delivery, its effect on transmembrane transport remains unclear. Here, we show that matrix stiffness is transmitted to the PM through the actomyosin cytoskeleton and thereby regulates nanoparticle (NP) uptake. Within a hepatocellular carcinoma-relevant stiffness range, matrix stiffening promoted excessive F-actin polymerization and stress-fiber formation, producing a mechanically damped PM-actin interface that resisted membrane deformation and suppressed NP uptake. Pharmacological and genetic perturbations indicated that this mechanical barrier was reversible. In vivo, β-aminopropionitrile-mediated tumor softening loosened ECM architecture, increased NP penetration, and promoted cellular uptake by reducing F-actin-associated mechanical resistance. Intratumoral spatial analyses and paired bilateral tumor experiments further supported local regulation of NP uptake by the actomyosin state under matched matrix conditions. Combined tumor softening and donafenib-loaded PLGA NPs reduced endpoint tumor weight by 87.8% relative to free donafenib but increased pulmonary metastasis, revealing a potential efficacy-safety trade-off. These findings identify a multiscale mechanical mechanism linking tumor-matrix mechanics to nanomedicine delivery and the PM-actin interface as a potential therapeutic target.