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

Matrix stiffening in hepatocellular carcinoma promotes F-actin polymerization that dampens plasma membrane deformation, reducing nanoparticle uptake by 87.8% in vivo.

• Why it matters: Understanding how tumor mechanics influence nanodrug delivery addresses a key barrier to effective solid tumor therapy, as extracellular and membrane-level forces limit nanoparticle penetration.
• What they did: The study combined pharmacological, genetic, and in vivo tumor softening approaches to show that matrix stiffness transmits mechanical signals through the actomyosin cytoskeleton, regulating nanoparticle uptake in tumor cells.
• The result: Loosening tumor ECM increased nanoparticle penetration and cellular uptake, significantly reducing tumor weight but also raising pulmonary metastasis, highlighting a potential therapeutic trade-off.