{"title":"Self-catalyzed nitric oxide nanocomplexes induce ferroptosis for cancer immunotherapy.","authors":"Lipeng Zhu, Dongliang Leng, Ziang Guo, Yuetao Zhao, Kam-Tong Leung, Yeneng Dai, Junnan Li, Qi Zhao","doi":"10.1016/j.jconrel.2024.11.048","DOIUrl":null,"url":null,"abstract":"<p><p>Ferroptosis, triggered by membrane lipid peroxidation (LPO) and diminished antioxidants, can be induced by intracellular iron (II, Fe<sup>2+</sup>). However, the role of nitric oxide (NO) in causing Fe<sup>2+</sup> overload for ferroptosis remains uncertain. This study reveals that NO can stimulate endogenous Fe<sup>2+</sup> release by upregulating heme oxygenase 1 (HMOX1) expression. Here, ferritin heavy chain (FHC) siRNA and hyaluronic acid (HA)-modified Arg-stabilized zinc peroxide (AZOSH), a non-ferrous-based nanoagent, is synthesized to trigger ferroptosis by inducing intracellular Fe<sup>2+</sup> overload. AZOSH, a self-catalyzed NO nanocomplex, effectively generates NO through a reaction of self-supplied Arginine (Arg) and hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), which promotes glutathione (GSH) consumption to downregulate glutathione peroxidase 4 (GPX4) expression and produces peroxynitrite (ONOO<sup>-</sup>) to enhance LPO. Meanwhile, NO promotes endo/lysosomal escape of siRNA by damaging membrane structures. Moreover, AZOSH significantly triggers Fe<sup>2+</sup> overload through the synergistic effects of NO-activated HMOX1 expression and FHC siRNA-mediated ferritin sequestration. Additionally, the released Zn<sup>2+</sup> from AZOSH induces oxidative stress by inhibiting mitochondrial function, further promoting ferroptosis. Consequently, AZOSH-mediated ferroptosis exhibits a strong cellular immunogenic response for T-cell activation and infiltration. Importantly, the integration of AZOSH with an anti-PD-1 antibody results in notable antitumor efficacy in vivo. Therefore, this study provides a novel concept of NO-induced ferroptosis, highlighting its role in enhancing PD-1-based immunotherapeutic efficacy.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":""},"PeriodicalIF":10.5000,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Controlled Release","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jconrel.2024.11.048","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Ferroptosis, triggered by membrane lipid peroxidation (LPO) and diminished antioxidants, can be induced by intracellular iron (II, Fe2+). However, the role of nitric oxide (NO) in causing Fe2+ overload for ferroptosis remains uncertain. This study reveals that NO can stimulate endogenous Fe2+ release by upregulating heme oxygenase 1 (HMOX1) expression. Here, ferritin heavy chain (FHC) siRNA and hyaluronic acid (HA)-modified Arg-stabilized zinc peroxide (AZOSH), a non-ferrous-based nanoagent, is synthesized to trigger ferroptosis by inducing intracellular Fe2+ overload. AZOSH, a self-catalyzed NO nanocomplex, effectively generates NO through a reaction of self-supplied Arginine (Arg) and hydrogen peroxide (H2O2), which promotes glutathione (GSH) consumption to downregulate glutathione peroxidase 4 (GPX4) expression and produces peroxynitrite (ONOO-) to enhance LPO. Meanwhile, NO promotes endo/lysosomal escape of siRNA by damaging membrane structures. Moreover, AZOSH significantly triggers Fe2+ overload through the synergistic effects of NO-activated HMOX1 expression and FHC siRNA-mediated ferritin sequestration. Additionally, the released Zn2+ from AZOSH induces oxidative stress by inhibiting mitochondrial function, further promoting ferroptosis. Consequently, AZOSH-mediated ferroptosis exhibits a strong cellular immunogenic response for T-cell activation and infiltration. Importantly, the integration of AZOSH with an anti-PD-1 antibody results in notable antitumor efficacy in vivo. Therefore, this study provides a novel concept of NO-induced ferroptosis, highlighting its role in enhancing PD-1-based immunotherapeutic efficacy.
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