肿瘤微环境特征为高浓度反应性氧物种(ROS)，这是用于对抗癌症的有效钥匙。因此，开发了针对肿瘤的纳米系统HFNP@GOX@PFC，由ROS裂解的铁基金属有机骨架、透明质酸(HA)、葡萄糖氧化酶(GOX)和全氟己烷(PFC)组成，用于肿瘤级联放大饥饿和化学动力治疗(CDT)。在体肿瘤高浓度过氧化氢(H2O2)的刺激下，HFNP@GOX@PFC在肿瘤细胞内可特异性分解并释放GOX、PFC和Fe2+，共同饥饿肿瘤并通过比较葡萄糖催化产生额外的H2O2，提供氧气以持续支持GOX介导的饥饿治疗，启动CDT和级联放大Fe2 +介导的Fenton反应，从而通过激活p53信号通路导致严重的肿瘤损伤。此外，HFNP@GOX@PFC通过激活NF-κB和MAPK信号通路，显著启动抗肿瘤免疫反应，重新教育肿瘤相关巨噬细胞(TAMs)。体外和体内实验结果共同证明，该纳米系统不仅持续启动饥饿治疗，还显著级联放大CDT和极化巨噬细胞，因此可以有效抑制肿瘤生长并具有良好的生物安全性。这种级联放大饥饿和CDT的功能纳米系统为肿瘤治疗提供了新的纳米平台。 ©2023作者。

Tumor microenvironment is characterized by the high concentration of reactive oxygen species (ROS), which is an effective key used to open the Pandora's Box against cancer. Herein, a tumor-targeted nanosystem HFNP@GOX@PFC composed of ROS-cleaved Fe-based metal-organic framework, hyaluronic acid (HA), glucose oxidase (GOX) and perfluorohexane (PFC) has been developed for tumor cascade amplified starvation and chemodynamic therapy (CDT). In response to the high concentration of hydrogen peroxide (H2O2) intratumorally, HFNP@GOX@PFC endocytosed by tumor cells can specially be disassembled and release GOX, PFC and Fe2+, which can collectively starve tumor and self-produce additional H2O2 via competitively glucose catalyzing, supply oxygen to continuous support GOX-mediated starvation therapy, initiate CDT and cascade amplify oxidative stress via Fe2+-mediated Fenton reaction, leading to the serious tumor damage with activated p53 signal pathway. Moreover, HFNP@GOX@PFC also significantly initiates antitumor immune response via re-educating tumor-associated macrophages (TAMs) by activating NF-κB and MAPK signal pathways. In vitro and in vivo results collectively demonstrate that nanosystem not only continuously initiates starvation therapy, but also pronouncedly cascade-amplify CDT and polarize TAMs, consequently efficiently inhibiting tumor growth with good biosafety. The functional nanosystem combined the cascade amplification of starvation and CDT provides a new nanoplatform for tumor therapy.© 2023. The Author(s).