Fisetin（FS）是一种潜在的口腔肿瘤治疗抗癌药物。然而，由于其疏水性和不稳定性，其临床应用受到了限制。生物活性聚合物基纳米系统在癌症治疗中具有巨大潜力。在这里，选择了不同的生物聚合物，用于其抗癌活性和靶向纳米颗粒制备能力，包括复糖（FU），玉米酸鸟氨酸（Zn）和透明质酸（HA）。选择的载药FS的交联Zn纳米粒子（ZFH），其中含有用于Zn纳米粒子稳定的HA和FU，显示出最合适的粒径（196 ± 6.53 nm），平均表面净电荷（-38.8 ± 1.47 mV）和包封效率（98 ± 1.2 %）。这是第一项利用HA和FU来双重靶向效应的研究，不仅用于稳定，还用于多个肿瘤靶标的靶向纳米粒子。ZHF的体外抗癌活性表现出独具匠心的SCC-4细胞摄取，在细胞毒性方面有显著作用。此外，使用4-硝基喹啉1-氧化物（4-NQO）诱导的口腔癌症状况评估了ZHF的效果；ZFH显著降低了OSCC特定的血清生物标志物水平，组织学肿瘤级别，并提高了caspase-3水平。此外，使用它们的特定标记评估了破坏两种关键的肿瘤调控细胞; TEC和CSC的潜力。详细介绍的ZFH纳米颗粒可以被认为是用于口腔癌治疗的有前途的靶向纳米疗法，具有增强的疗效和生存率。版权所有©2023。Elsevier B.V.发表。

Fisetin (FS) is an anticancer drug having potential role in oral tumors management. However, its clinical application is limited due to its hydrophobicity and instability. Bioactive polymers-based nanosystems have a great potential in cancer therapy. Herein, different biopolymers were selected for their anticancer activity and targeting ability for nanoparticles preparation namely; fucoidan (FU), zein (Zn) and hyaluronic acid (HA). The selected FS-loaded cross-linked Zn nanoparticles (ZFH) which contains HA& FU for Zn nanoparticles stabilization showed the most suitable particle size (196 ± 6.53 nm), mean surface net charge (-38.8 ± 1.47 mV) and entrapment efficiency (98 ± 1.2 %). This is the first study to utilize both HA &FU not only for stabilization but also for dual targeting effect due to their targeting ability to multiple tumor targets. In-vitro anticancer activity of ZHF revealed remarkable uptake by SCC-4 cells with significant cytotoxic action. Further, ZHF was appraised using 4-nitroquinoline 1-oxide (4-NQO)-induced oral cancer in-vivo; ZHF significantly reduced OSCC-specific serum biomarkers levels, histologic tumor grade and increased caspase-3 level. Moreover, potential of destroying two key tumor regulatory cells; TECs and CSCs, was evaluated using their specific markers. The elaborated ZFH nanoparticles could be considered as promising targeted nanotherapy for oral cancer treatment with enhanced efficacy and survival rate.Copyright © 2023. Published by Elsevier B.V.