5-氟尿嘧啶（5-FU）通常用作晚期 HCC 的化疗药物。然而，5-FU的有效性因耐药性的出现和靶向效率差而受到限制。 5-FU 与天然化合物的结合在 HCC 治疗中显示出了前景。在这项研究中，我们通过绿色合成程序制备了含有协同比例的5-FU和染料木黄酮（GEN）的无载体纳米颗粒（GEN-Cu-GEN@FUA）。所得的 GEN-Cu-GEN@FUA 纳米颗粒具有球形或近球形形状，动态尺寸为 129.3±40.1 nm，载药量高达约 21.40%（5-FU）和 61.48%（GEN）。在 Bel-7402 细胞中，这些纳米颗粒的 IC50 值比单独使用 5-FU 低约 3.6 倍，并且与单独使用 5-FU 相比，在 Bel-7402 荷瘤 BALB/c 小鼠中，肿瘤重量减少了 3.7 倍。重要的是，由于纳米颗粒对癌细胞功能障碍和细胞内谷胱甘肽消耗的显着放大具有协同作用，因此显示出可忽略不计的全身毒性。我们的研究结果表明，所开发的无载体纳米药物为金雀异黄素 (GEN) 铜 (II) 复合物和 5-FU 的共同递送提供了一个非常有前景的平台，且易于制造，并且在 HCC 协同治疗中具有巨大的临床转化潜力。© 2024.控制释放协会。

5-Fluorouracil (5-FU) is commonly used as a chemotherapeutic drug for advanced HCC. However, the effectiveness of 5-FU is limited by the emergence of resistance and poor targeting efficiency. Combining 5-FU with natural compounds has shown promise in HCC treatment. In this study, we prepared carrier-free nanoparticles (GEN-Cu-GEN@FUA) containing 5-FU and genistein (GEN) in a synergistic ratio via a green synthesis procedure. The resulting GEN-Cu-GEN@FUA nanoparticles had a spherical or near spherical shape, a dynamic size of 129.3 ± 40.1 nm, and a high drug loading content of approximately 21.40% (5-FU) and 61.48% (GEN). These nanoparticles exhibited approximately 3.6-fold lower IC50 value than 5-FU alone in Bel-7402 cells and resulted in a 3.7-fold greater reduction in tumor weight compared to 5-FU alone in Bel-7402 tumor-bearing BALB/c mice. Importantly, the nanoparticles showed negligible systemic toxicity due to their synergistic effect on cancer cell dysfunction and significant amplification of intracellular glutathione consumption. Our findings suggest that the developed carrier-free nanomedicines offer a highly promising platform for the co-delivery of genistein (GEN) copper(II) complexes and 5-FU, with easy fabrication and great potential for clinical translation in HCC synergistic therapy.© 2024. Controlled Release Society.