The abnormal mechanical microenvironment is a hallmark feature of solid tumors and plays a key role in immunotherapy resistance. The actin cytoskeleton can be finely tuned to control cell mechanics, which becomes a central target to regulate the tumor mechanical microenvironment (TMME). Here, we propose an actin-binding protein-modified magnetic nanomotor (ABP-MN) coupled with the rotating magnetic field (MF) to dynamically regulate the actin cytoskeleton for remodeling the TMME. ABP-MNs, with an ultrasmall diameter of 23 nm, intracellularly target the actin cytoskeleton and induce depolymerization via magneto-mechanical force under MF. Cancer-associated fibroblasts (CAFs) and tumor cells, which internalize ∼69.3% of ABP-MNs, are significantly tuned under MF with signs of a 7-fold decrease in tumor matrix stiffness, increased immune cell infiltration, and 95.8% tumor growth inhibition. This strategy unlocks a fresh field to reshape the TMME with the intracellular mechanical approach, thereby providing an effective mechano-based therapy in treating solid tumors.
Keywords: actin cytoskeleton; mechano-based therapy; rotating magnetic field; solid tumors; tumor mechanical microenvironment.