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/cm², 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.

Keywords

antibody–conjugated nanomedicine / focused ultrasound / nitric oxide–donor nanomedicine / tumor penetration / tumor-selective release

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2026 The Author(s). Interdisciplinary Medicine published by Wiley-VCH GmbH on behalf of Nanfang Hospital, Southern Medical University.