Zhan Shuyue, Cao Zhengwei, Li Jianwen, Chen Fanghui, Lai Xinning, Yang Wei, Teng Yong, Li Zibo, Zhang Weizhong, Xie Jin
Department of Chemistry, University of Georgia, Athens, Georgia 30602, United States.
Department of Hematology and Medical Oncology & Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, United States.
Bioconjug Chem. 2025 Jan 15;36(1):80-91. doi: 10.1021/acs.bioconjchem.4c00488. Epub 2024 Dec 16.
ATP (adenosine triphosphate) and HMGB1 (high mobility group box 1 protein) are key players in treatments that induce immunogenic cell death (ICD). However, conventional therapies, including radiotherapy, are often insufficient to induce ICD. In this study, we explore a strategy using nanoparticle-loaded macrophages as a source of ATP and HMGB1 to complement radiation-induced intrinsic and adaptive immune responses. To this end, we tested three inorganic particles, namely, iron oxide nanoparticles (ION), aluminum oxide nanoparticles (AON), and zinc oxide nanoparticles (ZON), with bone marrow-derived dendritic cells (BMDCs) and then in syngeneic tumor models. Our results showed that ION was the most effective of the three nanoparticles in promoting the secretion of ATP and HMGB1 from macrophages without negatively affecting macrophage survival. Secretions from ION-loaded macrophages can activate BMDCs. Intratumoral injection of ION-loaded macrophages significantly enhanced tumor infiltration and activation of dendritic cells and cytotoxic T cells. Moreover, exogenous ION macrophages can enhance the efficacy of radiotherapy. In addition, direct injection of ION can also enhance the efficacy of radiotherapy, which is attributed to ION uptake by and stimulation of endogenous macrophages. Instead of directly targeting cancer cells, our strategy targets macrophages and uses them as a secretory source of ATP and HMGB1 to enhance radiation-induced ICD. Our research introduces a new nanoparticle-based immunomodulatory approach that may have applications in radiotherapy and beyond.
三磷酸腺苷（ATP）和高迁移率族蛋白B1（HMGB1）是诱导免疫原性细胞死亡（ICD）治疗中的关键因子。然而，包括放疗在内的传统疗法往往不足以诱导ICD。在本研究中，我们探索了一种策略，即利用负载纳米颗粒的巨噬细胞作为ATP和HMGB1的来源，以补充辐射诱导的固有免疫和适应性免疫反应。为此，我们用骨髓来源的树突状细胞（BMDCs）测试了三种无机颗粒，即氧化铁纳米颗粒（ION）、氧化铝纳米颗粒（AON）和氧化锌纳米颗粒（ZON），然后在同基因肿瘤模型中进行了测试。我们的结果表明，在促进巨噬细胞分泌ATP和HMGB1方面，ION是这三种纳米颗粒中最有效的，且不会对巨噬细胞的存活产生负面影响。负载ION的巨噬细胞的分泌物可激活BMDCs。瘤内注射负载ION的巨噬细胞可显著增强肿瘤浸润以及树突状细胞和细胞毒性T细胞的激活。此外，外源性ION巨噬细胞可增强放疗效果。另外，直接注射ION也可增强放疗效果，这归因于ION被内源性巨噬细胞摄取并刺激其活性。我们的策略不是直接靶向癌细胞，而是靶向巨噬细胞，并将其作为ATP和HMGB1的分泌源来增强辐射诱导的ICD。我们的研究引入了一种新的基于纳米颗粒的免疫调节方法，可能在放疗及其他领域有应用价值。
