Xiong Yulong, Zhang Zhenhao, Liu Shangyu, Shen Lishui, Zheng Lihui, Ding Ligang, Liu Limin, Wu Lingmin, Hu Zhicheng, Li Le, Hu Zhao, Zhang Zhuxin, Zhou Likun, Xu Mengtong, Yao Yan
Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Int J Nanomedicine. 2024 Nov 29;19:12817-12833. doi: 10.2147/IJN.S487598. eCollection 2024.
Nanomedicine coated with cell membranes has attracted increasing attention for its enhanced targeting capability and biocompatibility. Based on previous research, we identified interferon regulatory factor 1 (IRF1)-mediated macrophage pyroptosis as a potential therapeutic target for myocarditis. Herein, we fabricated an innovative immune cell membrane-coated zeolitic imidazolate framework-8 (ZIF-8) nano-delivery platform and explored its effects on myocarditis.
ZIF-8 nanoparticles loaded with siRNA targeting IRF1 (siIRF1) were coated with a T lymphocyte-macrophage hybrid membrane (siIRF1@ZIF@HM NPs) via sonication and extrusion. The morphological and biological characteristics of the nanoparticles were evaluated using transmission electron microscopy (TEM) and dynamic light scattering (DLS). Cellular cytotoxicity was assessed by a cell counting kit-8 assay. Cellular uptake and endo-lysosomal escape in M1-differentiated macrophages were visualized via fluorescence microscopy. The targeting specificity and anti-myocarditis effects were evaluated in an experimental autoimmune myocarditis (EAM) mouse model. The anti-pyroptosis effects were assessed by Western blot analysis both in vivo and in vitro.
Transcriptional sequencing identified T lymphocytes and macrophages as suitable membrane sources. The ZIF-8 nanoparticles exhibited high siRNA loading capacity and pH responsiveness, enabling an efficient release of siIRF1 from endo-lysosomes to the cytoplasm in macrophages. The hybrid membrane coating enabled specific targeting of M1 macrophages both in vivo and in vitro. Furthermore, delivery of siIRF1 effectively suppressed IRF1 expression and inhibited pyroptosis in IFN-γ-stimulated macrophages. Intravenous injection of siIRF1@ZIF@HM NPs significantly alleviated myocarditis progression without evident side effects.
The siIRF1 nanotherapeutic approach shows potential for attenuating myocardial inflammation and mitigating myocarditis progression. Our study highlights the promise of this customized biomimetic nano-delivery system for treating inflammatory diseases.
细胞膜包覆的纳米医学因其增强的靶向能力和生物相容性而受到越来越多的关注。基于先前的研究，我们确定干扰素调节因子1（IRF1）介导的巨噬细胞焦亡是心肌炎的一个潜在治疗靶点。在此，我们构建了一种创新的免疫细胞膜包覆的沸石咪唑酯骨架-8（ZIF-8）纳米递送平台，并探讨其对心肌炎的影响。
通过超声处理和挤压，用T淋巴细胞-巨噬细胞混合膜包覆负载靶向IRF1的小干扰RNA（siIRF1）的ZIF-8纳米颗粒（siIRF1@ZIF@HM NPs）。使用透射电子显微镜（TEM）和动态光散射（DLS）评估纳米颗粒的形态和生物学特性。通过细胞计数试剂盒-8测定法评估细胞毒性。通过荧光显微镜观察M1分化巨噬细胞中的细胞摄取和内溶酶体逃逸。在实验性自身免疫性心肌炎（EAM）小鼠模型中评估靶向特异性和抗心肌炎作用。通过蛋白质免疫印迹分析在体内和体外评估抗焦亡作用。
转录测序确定T淋巴细胞和巨噬细胞为合适的膜来源。ZIF-8纳米颗粒表现出高siRNA负载能力和pH响应性，能够使siIRF1从巨噬细胞的内溶酶体有效释放到细胞质中。混合膜包覆在体内和体外均能实现对M1巨噬细胞的特异性靶向。此外，siIRF1的递送有效抑制了IRF1表达，并抑制了IFN-γ刺激的巨噬细胞中的焦亡。静脉注射siIRF1@ZIF@HM NPs可显著减轻心肌炎进展，且无明显副作用。
siIRF1纳米治疗方法显示出减轻心肌炎症和缓解心肌炎进展的潜力。我们的研究突出了这种定制的仿生纳米递送系统在治疗炎症性疾病方面的前景。
