Zhang Xu, Li Mao, Pang Xin, Wang Wan-Li, Wang Xiao-Chen, Shen Ze-Liang, Shi Rong-Jia, Tang Ya-Ling, Liang Xin-Hua
State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Dept. of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, No. 14, Sec.3, Renminnan Road, Chengdu Sichuan 610041, People's Republic of China.
State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Dept. of Oral Pathology, West China Hospital of Stomatology, Sichuan University, People's Republic of China.
Nanoscale. 2025 Apr 17;17(16):10277-10291. doi: 10.1039/d4nr05147e.
Ferroptosis-driven tumor ablation strategies based on nanotechnology could be achieved by increasing hydrogen peroxide (HO) concentrations or decreasing glutathione (GSH) levels. However, the intracellular antioxidative defense mechanisms endow the oral squamous cell carcinoma (OSCC) cells with ferroptosis resistance capacity. Therefore, injectable self-healing carboxymethyl chitosan (CMCS)/aldehyde-based hyaluronic acid (HA-CHO)/PVP-CuO (PCu)/polydopamine (PDA) (CHPP) hydrogels were developed to promote ferroptosis through increasing HO concentrations and decreasing GSH levels. The introduction of HA-CHO can directly target the CD44 receptor and form Schiff bonds CMCS to build the backbone of CHPP hydrogels. The CHPP hydrogels can responsively release HO to catalyze the production of hydroxyl radical (˙OH) chemodynamic therapy (CDT) in the tumor microenvironment (TME), sustained depletion of GSH through the dual action of Cu and ˙OH, and generate repeated high temperatures under photothermal therapy (PTT) for a direct OSCC-killing effect after the loading of PCu and PDA. In addition, the OSCC tissue RNA sequencing suggests that the differentially expressed genes of the CHPP hydrogels exerting the targeted OSCC therapy enrich the ferroptosis signaling pathways significantly. Then, liproxstatin-1 (a ferroptosis inhibitor) was utilized to recover the activation of glutathione peroxidase 4 (GPX4), which can weaken the therapeutic effect of CHPP on OSCC. The CHPP hydrogels are a promising strategy for the treatment of OSCC.
基于纳米技术的铁死亡驱动肿瘤消融策略可通过提高过氧化氢（HO）浓度或降低谷胱甘肽（GSH）水平来实现。然而，细胞内抗氧化防御机制赋予口腔鳞状细胞癌（OSCC）细胞铁死亡抵抗能力。因此，开发了可注射的自愈合羧甲基壳聚糖（CMCS）/醛基透明质酸（HA-CHO）/PVP-CuO（PCu）/聚多巴胺（PDA）（CHPP）水凝胶，通过提高HO浓度和降低GSH水平来促进铁死亡。HA-CHO的引入可直接靶向CD44受体并与CMCS形成席夫碱以构建CHPP水凝胶的骨架。CHPP水凝胶可在肿瘤微环境（TME）中响应性释放HO以催化产生羟基自由基（˙OH）进行化学动力学疗法（CDT），通过Cu和˙OH的双重作用持续消耗GSH，并在负载PCu和PDA后在光热疗法（PTT）下产生反复高温以直接杀死OSCC。此外，OSCC组织RNA测序表明，CHPP水凝胶发挥靶向OSCC治疗作用的差异表达基因显著富集铁死亡信号通路。然后，使用铁死亡抑制剂liproxstatin-1来恢复谷胱甘肽过氧化物酶4（GPX4）的活性，这会削弱CHPP对OSCC的治疗效果。CHPP水凝胶是一种有前景的OSCC治疗策略。
