Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, PR China.
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore.
Nat Commun. 2022 May 16;13(1):2688. doi: 10.1038/s41467-022-30436-y.
Inhibited immune response and low levels of delivery restrict starvation cancer therapy efficacy. Here, we report on the co-delivery of glucose oxidase (GOx) and indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan using a metal-organic framework (MOF)-based nanoreactor, showing an amplified release for tumor starvation/oxidation immunotherapy. The nanosystem significantly overcomes the biobarriers associated with tumor penetration and improves the cargo bioavailability owing to the weakly acidic tumor microenvironment-activated charge reversal and size reduction strategy. The nanosystem rapidly disassembles and releases cargoes in response to the intracellular reactive oxygen species (ROS). GOx competitively consumes glucose and generates ROS, further inducing the self-amplifiable MOF disassembly and drug release. The starvation/oxidation combined IDO-blockade immunotherapy not only strengthens the immune response and stimulates the immune memory through the GOx-activated tumor starvation and recruitment of effector T cells, but also effectively relieves the immune tolerance by IDO blocking, remarkably inhibiting the tumor growth and metastasis in vivo.
抑制的免疫反应和低水平的传递限制了饥饿癌症疗法的疗效。在这里，我们报告了使用金属-有机骨架（MOF）-基于纳米反应器共递送葡萄糖氧化酶（GOx）和吲哚胺 2,3-双加氧酶（IDO）抑制剂 1-甲基色氨酸，显示出增强的肿瘤饥饿/氧化免疫治疗释放。由于弱酸性肿瘤微环境激活的电荷反转和尺寸减小策略，该纳米系统显著克服了与肿瘤穿透相关的生物障碍，并提高了货物的生物利用度。纳米系统可快速响应细胞内活性氧（ROS）而解体并释放货物。GOx 竞争性地消耗葡萄糖并产生 ROS，进一步诱导自扩增 MOF 解体和药物释放。饥饿/氧化联合 IDO 阻断免疫疗法不仅通过 GOx 激活的肿瘤饥饿和效应 T 细胞的募集来增强免疫反应和刺激免疫记忆，而且还通过 IDO 阻断有效地缓解免疫耐受，显著抑制体内肿瘤生长和转移。
