Catalytic nanozyme-based tumor therapy is currently considered as a promising strategy in anti-tumor treatment, but it also has some disadvantages such as systemic toxicity, off-target, and non-specificity, leading to lowered therapeutic precision and efficacy in clinical curability. To overcome these limitations, herein we report a distinct strategy of nanocatalytic tumor precision therapy via tumor cell-specific CD44 targeted nanozyme-catalyzed cascade reactions. Briefly, the composite nanozyme ^CD44MMSN/AuNPs were assembled with two self-activable nanocatalysts including the inner core peroxidase-mimic Fe₃O₄ magnetic nanoparticles (MNPs), and the outer glucose oxidase-mimic AuNPs situated within large aperture mesoporous silicon (MMSN/AuNPs), and then functionalized with cell ligand hyaluronic acid (HA), which can specifically target transmembrane CD44 receptor of HepG2 tumor cells. In terms of catalysis, we found the coupled AuNPs effectively catalyzed glucose to produce H₂O₂, which was inversely catalyzed by Fe₃O₄ NPs and AuNPs to produce more hydroxyl radicals (•OH) in tumor microenvironment (TME). That is, this composite nanozyme performed self-activable reactive oxygen species (ROS)-mediated cascade reactions, and thereby resulted in significantly specific growth inhibition of hepatocellular carcinoma HepG2 cells. The present results also showed that the composite nanozyme ^CD44MMSN/AuNPs could specifically induce a greater number of HepG2 cell apoptosis and death. More importantly, we elucidated the mechanism of the composite nanozyme ^CD44MMSN/AuNPs via inducing HepG2 cell apoptosis and death from subcellular level. Therefore, this study represents an insightful paradigm for achieving nanocatalytic tumor precision therapy through rationally designing tumor cell-targeting inorganic nanozyme with self-activable cascade reactions.

目前，基于催化纳米酶的肿瘤治疗被认为是抗肿瘤治疗中的一种有前途的策略，但是它也具有一些缺点，例如全身毒性，脱靶和非特异性，导致治疗精度和临床治愈率降低。为了克服这些限制，本文中我们报告了通过肿瘤细胞特异性CD44靶向的纳米酶催化的级联反应进行纳米催化的肿瘤精确治疗的独特策略。简而言之，复合纳米酶^CD44 MMSN / AuNPs与包括内核过氧化物酶模拟的Fe ₃ O ₄在内的两种自激活纳米催化剂组装在一起。磁性纳米颗粒（MNP）和位于大孔径介孔硅（MMSN / AuNPs）中的外部葡萄糖氧化酶模拟AuNPs，然后用细胞配体透明质酸（HA）进行功能化，它可以特异性靶向HepG2肿瘤细胞的跨膜CD44受体。在催化方面，我们发现偶联的AuNPs有效地催化了葡萄糖生成H ₂ O ₂，而Fe ₂ O _4则对H ₂ O ₂进行了逆催化。NP和AuNP在肿瘤微环境（TME）中产生更多的羟基（•OH）。即，该复合纳米酶进行了可自活化的活性氧（ROS）介导的级联反应，从而导致肝细胞癌HepG2细胞的特异性特异性生长抑制。目前的结果还表明，复合纳米酶^CD44 MMSN / AuNPs可以特异性地诱导更多的HepG2细胞凋亡和死亡。更重要的是，我们阐明了复合纳米酶^CD44的机理MMSN / AuNPs通过诱导HepG2细胞凋亡和亚细胞水平的死亡。因此，本研究代表了通过合理设计具有自激活级联反应的靶向肿瘤细胞的无机纳米酶实现纳米催化肿瘤精确治疗的有见地的范例。