Ultrasound–triggered tumor‐selective nitric oxide release enhances tumor penetration of antibody–conjugated nanomedicine

Abstract The tumor vascular barrier restricts the penetration of antibody‐conjugated nanomedicine, severely limiting its therapeutic efficacy. Selective delivery of nitric oxide (NO) to tumors can modulate vascular permeability, thereby enhancing the penetration of antibody‐conjugated nanomedicine. Herein, we developed an ultrasound‐responsive NO‐releasing material, named HA‐SNO, based on a hyaluronic acid backbone, which releases NO upon exposure to ultrasound waves. After systemic administration of HA‐SNO, tumor‐localized release of NO was achieved using a focused ultrasound system operating at a low intensity (1 MHz, 2.0 W/cm 2 , 50% duty cycle). The released NO induced vasodilation and disrupted the tumor vascular barrier, thereby promoting extravasation and more homogeneous intratumoral distribution of HER2‐targeted antibody–conjugated nanomedicine (HER2–SN38). This strategy exhibited significantly enhanced anti‐tumor efficacy, with a tumor inhibition rate of 97.67%. These findings highlight the potential clinical utility of ultrasound‐triggered tumor‐selective delivery of NO in overcoming vascular barriers to drug delivery.