Reprogramming Tumor‐Associated Macrophages via Targeted NAT10 Inhibition to Enhance Colorectal Cancer Immunotherapy

Abstract This study introduces the Sono@NAT10 nanorobot for colorectal cancer (CRC) immunotherapy, designed to target NAT10 condensates in macrophages. Sono@NAT10, enclosed in a macrophage membrane using a metal–organic framework, shows stability under acidic conditions and releases NAT10 siRNA upon ultrasound activation. Flow cytometry and confocal imaging confirm effective macrophage targeting. Sequencing and proteomics reveal that NAT10 regulates SRSF2 protein stability, thereby promoting the transition of macrophages from the M2 to the M1 phenotype. In a CRC mouse model, Sono@NAT10 combined with anti‐PD‐1 (CD279) antibody inhibited tumor growth and enhances survival. These findings demonstrate the potential of Sono@NAT10 as a novel immunotherapeutic strategy for CRC by modulating NAT10 phase separation, providing a foundation for further exploration of its clinical application.