嵌入气囊的MIL-101(Fe)金属有机框架用于增强肿瘤微环境激活环，通过铁离子和灵芝多糖的战略性递送

Air bag-embedded MIL-101(Fe) metal-organic frameworks for an amplified tumor microenvironment activation loop through strategic delivery of iron ions and lentinan

Theranostics

影响因子:13.3

分区:医学1区 Top / 医学：研究与实验1区

发表日期:2024

作者: Tao Han, Yan Sun, Xi Jiang, Chengming Gong, Fei Kong, Yi Luo, Chang Ge, Congyan Liu, Yuping Liu, Yanfei Mou, Huangqin Zhang, Jianming Ju, Yan Chen, Ding Qu

DOI: 10.7150/thno.99303

摘要

背景：基于铁的纳米载体在引导肿瘤相关巨噬细胞（TAMs）极化向M1表型方面展现出潜力，这对于激活三阴性乳腺癌（TNBC）中的肿瘤微环境（TME）至关重要。然而，它们在实际应用中的效果受到Fe^{2+}/Fe^{3+}暴露不足和肿瘤中缺乏合适的协同剂的限制。方法：我们引入一种嵌入气囊的铁基MIL-101金属有机框架（MOF-MIL-101(Fe)），通过泡沫驱动的肿瘤同时递送Fe^{2+}/Fe^{3+}和灵芝多糖，以点燃TNBC中的TME。该系统命名为HM/Ef/LNT-MOF-MIL-101(Fe)，以纳米级MOF-MIL-101(Fe)为核心，嵌入NaHCO_3作为pH触发的气囊，静电吸附的灵芝多糖形成内壳，以及具有4T1细胞与红细胞混合膜的屏蔽壳层。结果：HM/Ef/LNT-MOF-MIL-101(Fe)能减轻血流中的非特异性捕获，但响应酸性肿瘤微环境，迅速生成大量二氧化碳气泡以解体MOF-MIL-101(Fe)。进入肿瘤后，灵芝多糖诱导的干扰素γ（IFN-γ）促进Fe^{2+}/Fe^{3+}的利用，从而增强铁死亡和Fenton样反应，通过“IFN-γ-铁死亡-ROS-Caspase-3”途径推动TAMs极化向M1。另外，HM/Ef/LNT-MOF-MIL-101(Fe)增加T淋巴细胞的浸润并减少调节性T细胞。这些级联免疫反应协同促进基于TAMs M1极化的放大TME激活环，显示出在抗癌效果方面的显著进展，并为多种联合治疗提供了潜力。结论：本研究采用“嵌入气囊”策略，实现了Fe^{2+}/Fe^{3+}和灵芝多糖的战略性共同递送，为调控肿瘤微环境提供了新工具。

Abstract

Background: Iron-based nanocarriers have demonstrated potential in redirecting tumor associated macrophages (TAMs) polarization towards the M1 phenotype, critical for activating the tumor microenvironment (TME) in triple negative breast cancer (TNBC). However, their real-world effectiveness is curtailed by insufficient Fe2+/3+ exposure and the absence of suitable synergists in tumors. Methods: We introduce an air bag-embedded iron-based MIL-101 metal-organic frameworks (MOFMIL-101(Fe)) for igniting the TME in TNBC through bubble-driven tumoral codelivery of Fe2+/3+ and lentinan. This system, named HM/Ef/LNT-MOFMIL-101(Fe), features nano-sized MOFMIL-101(Fe) as the core, embedded NaHCO3 as a pH-triggered air bag, electrostatically-adsorbed lentinan forming the inner shell, and a shield shell with 4T1&red blood cell hybrid membrane. Results: HM/Ef/LNT-MOFMIL-101(Fe) can mitigate non-specific capture in the bloodstream but respond to the acidic tumor milieu, rapidly generating a burst of CO2 bubbles to disassemble MOFMIL-101(Fe). Upon entering tumors, lentinan-induced interferon-γ (IFN-γ) enable Fe2+/3+ facilitating an enhanced ferroptosis and Fenton-like reaction, pushing TAMs towards M1 polarization via the "IFN-γ-ferroptosis-ROS-Caspase-3" pathway. Moreover, HM/Ef/LNT-MOFMIL-101(Fe) increases the infiltration of T lymphocytes and decreases regulatory T cells. These cascading immune responses synergistically foster a loop of amplified TME activation based on TAMs M1 polarization, showcasing notable advancements in anticancer effectiveness and promise for various combination therapies. Conclusion: This study utilizes an "embedded air-bag" strategy to achieve strategic codelivery of Fe2+/3+ and lentinan, providing a new tool for engineering the TME.