State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, P. R. China.
School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China.
Adv Mater. 2024 Jan;36(2):e2307752. doi: 10.1002/adma.202307752. Epub 2023 Nov 23.
Tumor cells movement and migration are inseparable from the integrity of lipid rafts and the formation of lamellipodia, and lipid rafts are also a prerequisite for the formation of lamellipodia. Therefore, destroying the lipid rafts is an effective strategy to inhibit tumor metastasis. Herein, a multi-enzyme co-expressed nanomedicine: cholesterol oxidase (CHO) loaded Co─PN single-atom nanozyme (Co─PN SA/CHO) that can up-regulate cellular oxidative stress, disrupt the integrity of lipid rafts, and inhibit lamellipodia formation to induce anti-metastasis tumor therapy, is developed. In this process, Co─PN SA can catalyze oxygen (O ) and hydrogen peroxide (H O ) to generate reactive oxygen species (ROS) via oxidase-like and Fenton-like properties. The doping of P atoms optimizes the adsorption process of the intermediate at the active site and enhances the ROS generation properties of nanomedicine. Meantime, O produced by catalase-like catalysis can combine with excess cholesterol to generate more H O under CHO catalysis, achieving enhanced oxidative damage to tumor cells. Most importantly, cholesterol depletion in tumor cells also disrupts the integrity of lipid rafts and inhibits the formation of lamellipodia, greatly inhibiting the proliferation and metastasis of tumor cells. This strategy by up-regulating cellular oxidative stress and depleting cellular cholesterol constructs a new idea for anti-metastasis-oriented cancer therapy strategies.
肿瘤细胞的运动和迁移离不开脂筏的完整性和片状伪足的形成，而脂筏也是片状伪足形成的前提。因此，破坏脂筏是抑制肿瘤转移的有效策略。在此，开发了一种多酶共表达的纳米药物：负载胆固醇氧化酶（CHO）的 Co─PN 单原子纳米酶（Co─PN SA/CHO），它可以上调细胞氧化应激，破坏脂筏的完整性，并抑制片状伪足的形成，从而诱导抗转移肿瘤治疗。在这个过程中，Co─PN SA 可以通过氧化酶样和芬顿样特性，催化氧气（O ）和过氧化氢（H O ）生成活性氧物种（ROS）。磷原子的掺杂优化了中间物在活性位点的吸附过程，并增强了纳米药物的 ROS 生成特性。同时，过氧化物酶样催化产生的 O 可以在 CHO 催化下与过量胆固醇结合生成更多的 H O ，实现对肿瘤细胞的增强氧化损伤。最重要的是，肿瘤细胞中胆固醇的耗竭也破坏了脂筏的完整性并抑制了片状伪足的形成，从而极大地抑制了肿瘤细胞的增殖和转移。这种通过上调细胞氧化应激和耗竭细胞胆固醇来构建的策略为抗转移导向的癌症治疗策略提供了新的思路。
