Wang Xiaoqi, Huang Ruihao, Wu Wei, Xiong Jingkang, Wen Qin, Zeng Yunjing, Chen Ting, Li Jiali, Zhang Cheng, Zhong Jiang F, Yang Shijie, Zhang Xi
Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing 400037, China.
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States.
Acta Biomater. 2023 Feb;157:381-394. doi: 10.1016/j.actbio.2022.11.007. Epub 2022 Nov 12.
Chemotherapy resistance and the tumor immune microenvironment are dual reasons for the poor therapeutic efficacy of treating acute myeloid leukemia (AML), causing suboptimal clinical outcomes and high relapse rates. Activation of the stimulator of interferon genes (STING) pathway based on innate immunity can effectively improve antitumor immunity. However, traditional STING agonists are limited due to their easy degradation and difficult membrane transport. Here, a bioinspired nanomedicine synergizing chemo- and immunotherapy was developed by activating the STING pathway for targeted and systemic AML cell damage. We show that a leukemia cell membrane (LCM)-camouflaged hollow MnO nanocarrier (HM) with encapsulated doxorubicin (DOX) (denoted LHMD) could bind specifically to AML cells with a homologous targeting effect. Then, MnO was decomposed into Mn in response to endosomal acid and glutathione (GSH), which improved the magnetic resonance imaging (MRI) signal for AML detection and activated the STING pathway. In mouse models, LHMD was confirmed to eradicate established AML and prevent the engraftment of AML cells. The percentages of T-helper 1 (Th1) and T-helper 17 (Th17) cells and the concentrations of type I interferon (IFN-Ⅰ) and proinflammatory cytokines increased, while the percentage of T-helper 2 (Th2) cells decreased, reflecting the anti-AML immune response induced by Mn after treatment with LHMD. This nanotechnology-based therapeutic regimen may represent a generalizable strategy for generating an anti-leukemia immune response. STATEMENT OF SIGNIFICANCE: Relapse and chemotherapy refractoriness are main causes for the dismal prognosis of AML, making it urgent to develop more effective anti-AML therapies. This study proposes an innovative strategy to combat this issue by designing a biomimetic BM-targeted nanomedicine based on a MnO nano-carrier to rationally deliver chemotherapeutic agents and to trigger Mn mediated STING pathway activation for potent immune- and chemotherapy against AML cells. Hence, the nanomedicine design addresses the challenges associated with AML therapy and proposes a promising strategy to improve the therapeutic efficacy against AML.
化疗耐药性和肿瘤免疫微环境是急性髓系白血病（AML）治疗效果不佳的双重原因，导致临床疗效欠佳和高复发率。基于先天免疫的干扰素基因刺激物（STING）通路的激活可有效提高抗肿瘤免疫力。然而，传统的STING激动剂由于易于降解和膜转运困难而受到限制。在此，通过激活STING通路以实现对AML细胞的靶向和全身性损伤，开发了一种协同化疗和免疫治疗的仿生纳米药物。我们表明，一种包裹有阿霉素（DOX）的白血病细胞膜（LCM）伪装的中空MnO纳米载体（HM）（命名为LHMD）可以与AML细胞特异性结合，具有同源靶向作用。然后，MnO在内体酸性环境和谷胱甘肽（GSH）的作用下分解为Mn，这改善了用于AML检测的磁共振成像（MRI）信号并激活了STING通路。在小鼠模型中，LHMD被证实可根除已建立的AML并防止AML细胞植入。辅助性T细胞1（Th1）和辅助性T细胞17（Th17）的百分比以及I型干扰素（IFN-Ⅰ）和促炎细胞因子的浓度增加，而辅助性T细胞2（Th2）的百分比降低，这反映了用LHMD治疗后Mn诱导的抗AML免疫反应。这种基于纳米技术的治疗方案可能代表了一种可推广的产生抗白血病免疫反应的策略。重要性声明：复发和化疗难治性是AML预后不佳的主要原因，因此迫切需要开发更有效的抗AML疗法。本研究提出了一种创新策略来解决这一问题，即设计一种基于MnO纳米载体的仿生骨髓靶向纳米药物，以合理递送化疗药物并触发Mn介导的STING通路激活，从而对AML细胞进行有效的免疫和化疗。因此，该纳米药物设计解决了与AML治疗相关的挑战，并提出了一种有前景的提高抗AML治疗疗效的策略。
