Nanotherapy based on thermochemotherapy has boomed as a promising alternative for oncotherapy due to the enhanced permeability and retention (EPR) effect. However, a lack of self-targeting capacity prevents nanotherapy from efficiently accumulating in tumor tissue and internalizing into tumor cells, resulting in a suboptimal therapeutic effect. To overcome these bottlenecks, a kind of methotrexate (MTX)-soybean phospholipid (SPC) inclusion complex (MTX-SPC)-modified graphene oxide (CGO) nanotherapy (CGO-MTX-SPC) is constructed by CGO nanosheets as a supporter for MTX-SPC, thereby realizing active-targeting and synergistic thermochemotherapy. As an FDA-approved chemotherapeutic drug, MTX can be regarded as a tumor-targeting enhancer against the folate receptor on account of its similar structure to folic acid (FA). The fabricated CGO-MTX-SPC has a sheet shape with a size of ca. 109 nm and tumor microenvironment-responsive on-demand drug release. It is worth noting that the physiological stability of CGO-MTX-SPC is better than that of CGO while displaying an improved photothermal effect. In addition, CGO-MTX-SPC can specifically recognize tumor cells and then achieve on-demand drug burst release by dual stimuli of internal lysosomal acidity and an external laser. Moreover, in vivo experimental results further demonstrate that CGO-MTX-SPC displays significant enrichment at the tumor location by active targeting mechanisms due to the introduction of MTX-SPC, endowing the synergistic thermochemotherapy effect upon 808 nm laser irradiation and almost thorough tumor elimination while significantly erasing undesirable side effects. Taken together, the design idea of our nanotherapy not only provides a potential tumor-targeting therapeutic strategy but also broadens the drug payload method of two-dimensional nanomaterials.

由于增强的渗透性和保留 (EPR) 效应，基于热化学疗法的纳米疗法已成为一种有前途的肿瘤疗法替代方案。然而，自靶向能力的缺乏阻碍了纳米疗法在肿瘤组织中有效积累并内化到肿瘤细胞中，从而导致治疗效果欠佳。为了克服这些瓶颈，一种甲氨蝶呤（MTX）-大豆磷脂（SPC）包合物（MTX-SPC）-改性氧化石墨烯（CGO）纳米疗法（CGO-MTX-SPC）是由CGO纳米片作为MTX的载体构建的-SPC，从而实现主动靶向和协同热化学疗法。作为FDA批准的化疗药物，MTX由于其结构与叶酸（FA）相似，可被视为针对叶酸受体的肿瘤靶向增强剂。约 109 nm 和肿瘤微环境响应按需药物释放。值得注意的是，CGO-MTX-SPC 的生理稳定性优于 CGO，同时表现出改善的光热效应。此外，CGO-MTX-SPC可以特异性识别肿瘤细胞，然后通过内部溶酶体酸度和外部激光的双重刺激实现按需药物突释。此外，体内实验结果进一步表明，由于MTX-SPC的引入，CGO-MTX-SPC通过主动靶向机制在肿瘤位置显示出显着富集，赋予808 nm激光照射协同热化疗效果，几乎彻底消除肿瘤，同时显着消除不良侧效果。总之，我们的纳米疗法的设计理念不仅提供了一种潜在的肿瘤靶向治疗策略，而且拓宽了二维纳米材料的药物负载方法。