肝细胞癌（HCC）的不良预后仍然是全世界亟待解决的挑战。因此，将药物和靶向短肽组装在一起构建新型药物递送策略对于肝癌的靶向和协同治疗至关重要。在此，通过结合氧化石墨二炔（GDYO）作为载药平台、特异性肽（SP94-PEG）作为靶向HCC细胞的矛、索拉非尼、阿霉素-Fe2（DOX-Fe2），构建了高效纳米药物递送策略）和siRNA（SLC7A11-i）作为武器，对HCC细胞发挥三路协同攻击作用。在这项工作中，SP94-PEG和GDYO形成具有HCC靶向特性的纳米片，与亚铁离子连接的化疗药物DOX增加了HCC细胞中的游离铁库，并与索拉非尼协同作用诱导细胞铁死亡。作为铁死亡的关键基因，干扰SLC7A11的表达使得肝癌细胞的铁死亡效应更容易、更强、更持久。通过基因干扰、药物协同、短肽靶向等方式，降低化疗药物的毒副作用。多功能纳米药物GDYO@SP94/DOX-Fe2/索拉非尼/SLC7A11-i（MNMG）与传统药物相比，具有靶向性强、稳定性好、能够持续诱导肿瘤细胞铁死亡等优点，具有潜在的临床应用价值.© 2024。作者。

The poor prognosis of hepatocellular carcinoma (HCC) is still an urgent challenge to be solved worldwide. Hence, assembling drugs and targeted short peptides together to construct a novel medicine delivery strategy is crucial for targeted and synergy therapy of HCC. Herein, a high-efficiency nanomedicine delivery strategy has been constructed by combining graphdiyne oxide (GDYO) as a drug-loaded platform, specific peptide (SP94-PEG) as a spear to target HCC cells, sorafenib, doxorubicin-Fe2+ (DOX-Fe2+), and siRNA (SLC7A11-i) as weapons to exert a three-path synergistic attack against HCC cells. In this work, SP94-PEG and GDYO form nanosheets with HCC-targeting properties, the chemotherapeutic drug DOX linked to ferrous ions increases the free iron pool in HCC cells and synergizes with sorafenib to induce cell ferroptosis. As a key gene of ferroptosis, interference with the expression of SLC7A11 makes the ferroptosis effect in HCC cells easier, stronger, and more durable. Through gene interference, drug synergy, and short peptide targeting, the toxic side effects of chemotherapy drugs are reduced. The multifunctional nanomedicine GDYO@SP94/DOX-Fe2+/sorafenib/SLC7A11-i (MNMG) possesses the advantages of strong targeting, good stability, the ability to continuously induce tumor cell ferroptosis and has potential clinical application value, which is different from traditional drugs.© 2024. The Author(s).