Ultrasonic-Controlled Drug Release Prevents Protumorigenic Transition and Improves Sequential Targeting Effect to Enhance Treatment of Residual Hepatocellular Carcinoma

Insufficient radio-frequency ablation (IRFA) of hepatocellular carcinoma accelerates the recurrence of residual tumor, leading to a poor prognosis. Neutrophils (NEs), as the initial leukocytes to infiltrate the IRFA-associated inflammatory area, were utilized as drug carriers due to their inherent chemotactic properties for targeted delivery of chemotherapy drugs to the inflammatory site where residual tumor persists post-IRFA. Previous research has highlighted that the immunosuppressive cytokines in the tumor microenvironment could promote the transition of NEs into a protumorigenic phenotype. However, it is unclear whether NEs used as drug delivery carriers undergo similar changes and how this transition affects treatment effectiveness. Here, we present novel findings demonstrating the phenotypic transition of NEs in the residual tumor microenvironment from an antitumorigenic to a protumorigenic state following IRFA treatment. More critically, we found for the first time that NE carriers undergo a comparable phenotypic transition in the residual tumor, thereby attenuating the therapeutic outcome. Ingeniously, coloading NE carriers with perfluorohexane not only enabled ultrasound imaging but also facilitated spatiotemporally controllable drug release through ultrasound irradiation, thus preventing the protumorigenic transition of NE carriers and maintaining an inflammatory microenvironment at the residual tumor zone. This significantly improved the sequential targeting effect of NE carriers and ultimately enhanced the treatment of residual tumor post-IRFA. Our study provided novel insights into the modulatory role of the immune microenvironment on the phenotypic transition of live NE carriers in the drug delivery system and presented a strategy to prevent adverse effects and enhance residual tumor treatment.