Actin-Targeted Magnetic Nanomotors Mechanically Modulate the Tumor Mechanical Microenvironment for Cancer Treatment
Xing Fan, Haotian Chen, Yuan Li, Qishuai Feng, Tao Feng, Chang Xu, Xiaolei Chen, Rui Gao, Yingying Wang, Xinyu Guo, Chenkai Sun, Cheng Lv, Yu Cheng
Abstract
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.