The formimidoyltransferase cyclodeaminase (FTCD) gene encodes an enzyme required for the catabolism of histidine and tetrahydrofolate (THF). Previous studies showed that FTCD plays a role as a tumour suppressor gene in hepatocellular carcinoma (HCC). It is unknown whether the restoration of functional FTCD may exhibit an anti-tumour effect on HCC. This study constructed a delivery system based on hollow mesoporous organosilica nanotheranostics (HMON) capable of efficiently loading Mn ions and FTCD plasmids. This study showed that the Mn-doped and FTCD-loaded nanoparticles (HMON@Mn-PEI@FTCD) could efficiently induce the expression of FTCD and achieve enhanced magnetic resonance imaging. In vitro results demonstrated that the upregulation of FTCD induced by HMON@Mn-PEI@FTCD nanoparticles dramatically reduced intracellular THF levels, inhibited of NADPH/NADP+ and GSH/GSSG ratios, and induced reactive oxygen species generation and mitochondrial oxidative stress. As a result, cytochrome c release increased with the opening of the mitochondrial permeability transition pore, which finally activated the caspase-dependent cell apoptosis pathway. Therefore, our designed HMON@Mn-PEI@FTCD could induce apoptosis by activating the mitochondria-mediated apoptosis signalling pathway, and finally significantly suppressed the proliferation of HCC both in vitro and in vivo, which provides an effective strategy for the treatment of HCC.

甲酰转移酶环脱氨酶 ( FTCD ) 基因编码组氨酸和四氢叶酸 (THF) 分解代谢所需的酶。先前的研究表明，FTCD在肝细胞癌 (HCC) 中起到抑癌基因的作用。尚不清楚功能性 FTCD 的恢复是否可能对 HCC 表现出抗肿瘤作用。本研究构建了一种基于中空介孔有机硅纳米治疗学 (HMON) 的递送系统，能够有效地装载 Mn 离子和 FTCD 质粒。该研究表明，Mn掺杂和FTCD负载的纳米粒子（HMON@Mn-PEI@FTCD）可以有效地诱导FTCD的表达并实现增强的磁共振成像。体外结果表明，由 HMON@Mn-PEI@FTCD 纳米颗粒诱导的 FTCD 上调显着降低了细胞内 THF 水平，抑制了 NADPH/NADP+ 和 GSH/GSSG 比率，并诱导了活性氧的产生和线粒体氧化应激。结果，随着线粒体通透性转换孔的打开，细胞色素c的释放增加，最终激活了caspase依赖的细胞凋亡途径。因此，我们设计的HMON@Mn-PEI@FTCD可以通过激活线粒体介导的凋亡信号通路诱导细胞凋亡，最终在体外和体内显着抑制HCC的增殖，为HCC的治疗提供了有效的策略。