Huang Yongquan, Pi Songying, Chen Hui, Zhang Shushan, Xian Jianzhong, Lin Yuhong, Chen Jiaxing, Ye Qing, Ye Feile, Huang Yin, Yu Hailing, Su Zhongzhen
Department of Ultrasound, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China.
Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China.
Biomater Res. 2025 Jan 29;29:0114. doi: 10.34133/bmr.0114. eCollection 2025.
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.
肝细胞癌的射频消融不足（IRFA）会加速残留肿瘤的复发，导致预后不良。中性粒细胞（NEs）作为最早浸润IRFA相关炎症区域的白细胞，因其固有的趋化特性被用作药物载体，用于将化疗药物靶向递送至IRFA后残留肿瘤所在的炎症部位。先前的研究强调，肿瘤微环境中的免疫抑制细胞因子可促进中性粒细胞向促肿瘤表型转变。然而，尚不清楚用作药物递送载体的中性粒细胞是否会发生类似变化，以及这种转变如何影响治疗效果。在此，我们展示了新的研究结果，证明IRFA治疗后，残留肿瘤微环境中的中性粒细胞从抗肿瘤表型转变为促肿瘤表型。更关键的是，我们首次发现中性粒细胞载体在残留肿瘤中经历了类似的表型转变，从而削弱了治疗效果。巧妙的是，将全氟己烷与中性粒细胞载体共负载，不仅能够实现超声成像，还能通过超声照射促进药物的时空可控释放，从而防止中性粒细胞载体的促肿瘤转变，并在残留肿瘤区域维持炎症微环境。这显著提高了中性粒细胞载体的序贯靶向效果，最终增强了IRFA后残留肿瘤的治疗效果。我们的研究为免疫微环境对药物递送系统中活性中性粒细胞载体表型转变的调节作用提供了新见解，并提出了一种预防不良反应和增强残留肿瘤治疗的策略。
