Cascade reaction-mediated efficient ferroptosis synergizes with immunomodulation for high-performance cancer therapy,Biomaterials Science

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Cascade reaction-mediated efficient ferroptosis synergizes with immunomodulation for high-performance cancer therapy
Biomaterials Science ( IF 5.8 ) Pub Date : 2020-09-11 , DOI: 10.1039/d0bm01168a
Zhaowei Li _{1,

2,

3,

4,

5} , Long Rong _{1,

2,

3,

4,

5}

Affiliation

Given that traditional anticancer therapies fail to significantly improve the prognoses, new modalities with high efficiency are urgently needed. Herein, a nanozyme-based formulation, which synergized efficient ferroptosis with immunomodulation for high-performance cancer therapy, was constructed. Specifically, ultrasmall CaO₂ and Fe₃O₄ nanoparticles (NPs) were co-loaded onto dendritic mesoporous silica nanoparticles (DMSN) followed by coating with the pH-responsive membrane, which could not only prevent the leakage of the cargos but also realize tumor-specific release. After intravenous injection, the H⁺ ions in a weak acidic microenvironment triggered the cascade reaction by reacting with CaO₂ and produced abundant H₂O₂ in the tumor tissue. Subsequently, the produced H₂O₂ was catalyzed into toxic hydroxyl radicals (˙OH) through a Fenton-like reaction mediated by Fe₃O₄ NPs and induced ferroptosis, which promoted the release of tumor-associated antigens and generated an immunogenic tumor microenvironment (TME). Furthermore, immunomodulation was achieved by the polarization of tumor-associated macrophages (TAMs) induced by pH changes. The efficient ferroptosis and immunomodulation cooperatively paved the way for the inhibition of tumors. Beyond the inhibition of the primary tumor, the formulation could also efficiently provoke the immune response to exert a potent anticancer effect through combining with an immune checkpoint blockade. After being co-loaded with aCD47, the phagocytes could be stimulated and enhance the uptake efficiency of the tumor antigens to realize efficient immunotherapy with few abnormalities. Our approach thus offers a versatile formulation to realize the synergism of ferroptosis and immunomodulation/immunotherapy for high-performance cancer therapy.

中文翻译：

级联反应介导的高效铁锈病与免疫调节协同作用，用于高性能癌症治疗

鉴于传统的抗癌疗法不能显着改善预后，迫切需要高效的新方法。在此，构建了一种基于纳米酶的制剂，该制剂可将高效的促脚病病学与免疫调节协同作用，用于高性能癌症治疗。具体而言，将超小型CaO ₂和Fe ₃ O ₄纳米颗粒（NPs）共同装载到树状中孔二氧化硅纳米颗粒（DMSN）上，然后用pH响应膜进行涂覆，这不仅可以防止货物泄漏，而且可以实现肿瘤特定的版本。静脉注射后，弱酸性微环境中的H ⁺离子通过与CaO ₂反应触发级联反应并在肿瘤组织中产生丰富的H ₂ O ₂。随后，通过Fe ₃ O ₄介导的芬顿样反应将生成的H ₂ O ₂催化为有毒的羟基自由基（˙OH）NPs和诱导的肥大病，促进了肿瘤相关抗原的释放，并产生了免疫原性的肿瘤微环境（TME）。此外，通过pH变化诱导的肿瘤相关巨噬细胞（TAM）的极化实现了免疫调节。有效的肥大病和免疫调节共同为抑制肿瘤铺平了道路。除了抑制原发性肿瘤外，该制剂还可以通过与免疫检查点封锁相结合，有效激发免疫反应，发挥有效的抗癌作用。与aCD47共同加载后，可以刺激吞噬细胞并提高肿瘤抗原的摄取效率，从而实现几乎没有异常的有效免疫治疗。

更新日期：2020-10-05

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