Renal Clearable Ultrasmall Single-Crystal Fe Nanoparticles for Highly Selective and Effective Ferroptosis Therapy and Immunotherapy
Renal Clearable Ultrasmall Single-Crystal Fe Nanoparticles for Highly Selective and Effective Ferroptosis Therapy and Immunotherapy
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DOI：
10.1021/jacs.1c07471
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发表时间：
2021-09-29
影响因子：
15
通讯作者：
Sun, Xiaolian
中科院分区：
文献类型：
--
作者：
Liang, Huan;Wu, Xiyao;Sun, Xiaolian
铁基纳米颗粒由于其通过催化芬顿反应诱导铁凋亡并进一步增强免疫治疗的能力而引起了人们的广泛关注。然而，目前的铁基纳米颗粒需要与其他治疗配合使用，或者由于其低活性氧产生功效而以高剂量应用于有效治疗。在这里，我们合成了超小单晶Fe纳米颗粒（bcc-USINPs），它在正常生理环境中保持稳定，但在肿瘤微环境中高度活跃，因为Fe 3 O 4外壳的选择性酸蚀刻和Fe（0）核心的暴露。bcc-USINPs在很低的浓度下就能有效诱导肿瘤细胞的铁凋亡和免疫原性细胞死亡。静脉注射iRGD-bcc-USINPs 1 mg/kg三个剂量组均能有效抑制肿瘤生长，促进树突状细胞成熟，触发适应性T细胞反应。结合程序性死亡配体1（PD-L1）免疫检查点阻断免疫疗法，iRGD-bcc-USINP介导的铁凋亡疗法极大地增强了免疫应答并产生了强免疫记忆。此外，这些USINPs可快速经肾脏排泄，在正常组织中无副作用。这些iRGD-bccUSINPs提供了一种简单、安全、有效和选择性肿瘤响应的Fe（0）递送系统，用于基于铁凋亡的免疫治疗。
Iron-based nanoparticles have attracted much attention because of their ability to induce ferroptosis via a catalyzing Fenton reaction and to further potentiate immunotherapy. However, current iron-based nanoparticles need to be used in cooperation with other treatments or be applied in a high dose for effective therapy because of their low reactive oxygen species production efficacy. Here, we synthesized ultrasmall single-crystal Fe nanoparticles (bcc-USINPs) that stayed stable in a normal physiological environment but were highly active in a tumor microenvironment because of the selective acidic etching of an Fe3O4 shell and the exposure of the Fe(0) core. The bcc-USINPs could efficiently induce tumor cell ferroptosis and immunogenetic cell death at a very low concentration. Intravenous injection of iRGD-bcc-USINPs at three doses of 1 mg/kg could effectively suppress the tumor growth, promote the maturation of dendritic cells, and trigger the adaptive T cell response. Combined with programmed death-ligand 1 (PD-L1) immune checkpoint blockade immunotherapy, the iRGD-bcc-USINP-mediated ferroptosis therapy greatly potentiated the immune response and developed strong immune memory. In addition, these USINPs were quickly renal excreted with no side effects in normal tissues. These iRGD-bccUSINPs provide a simple, safe, effective, and selectively tumor-responsive Fe(0) delivery system for ferroptosis-based immunotherapy.