基于外泌体的 circRNA mSCAR 线粒体递送通过协调巨噬细胞激活缓解脓毒症,Advanced Science

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基于外泌体的 circRNA mSCAR 线粒体递送通过协调巨噬细胞激活缓解脓毒症
Advanced Science ( IF 14.3 ) Pub Date : 2023-03-25 , DOI: 10.1002/advs.202205692
Li Fan ₁ , Li Yao ₂ , Zhelong Li ₃ , Zhuo Wan ₄ , Wenqi Sun ₃ , Shuo Qiu ₃ , Wei Zhang ₅ , Dan Xiao ₁ , Liqiang Song ₆ , Guodong Yang ₇ , Yi Zhang ₈ , Mengying Wei ₇ , Xuekang Yang ₁

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脓毒症是最常见的死亡原因之一，与不受控制的全身炎症密切相关。M1 巨噬细胞极化失调是严重炎症的主要原因。在这项研究中，揭示了 circRNA SCAR（脂肪性肝炎相关的 circRNA ATP5B 调节剂）的小鼠同系物，在下文中表示为 circRNA mSCAR，在败血症小鼠的巨噬细胞中减少，这与过度的 M1 极化相关。为了在线粒体中恢复 circRNA mSCAR，用 circRNA mSCAR 封装的外泌体进一步用聚-D-赖氨酸-接枝-三苯基膦（TPP-PDL）电穿孔，因此当外泌体被受体吞噬时，TPP-PDL 促进结合的 circRNA 递送到线粒体中细胞。在体内脓毒症小鼠模型和体外细胞模型中，结果表明，基于外泌体的线粒体递送系统优先将 circRNA mSCAR 递送到巨噬细胞中的线粒体中，有利于巨噬细胞向 M2 亚型极化。因此，全身性炎症通过基于外泌体的 circRNA mSCAR 线粒体递送而减弱，同时死亡率降低。总的来说，这些结果揭示了 circRNA mSCAR 在脓毒症中的关键作用，并提供了一种通过基于外泌体的线粒体递送 circRNA mSCAR 来减轻脓毒症的有前途的方法。

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Exosome-Based Mitochondrial Delivery of circRNA mSCAR Alleviates Sepsis by Orchestrating Macrophage Activation

Sepsis is one of the most common causes of death, which is closely related to the uncontrolled systemic inflammation. Dysregulation of M1 macrophage polarization is the primary contributor to serious inflammation. In this study, it is revealed that the murine homologue of circRNA SCAR (steatohepatitis-associated circRNA ATP5B regulator), denoted as circRNA mSCAR hereafter, decreases in the macrophages of septic mice, which correlates with the excessive M1 polarization. To restore circRNA mSCAR in mitochondria, exosomes encapsulated with circRNA mSCAR are further electroporated with poly-D-lysine-graft-triphenylphosphine (TPP-PDL), and thus TPP-PDL facilitates the bound circRNA delivered into mitochondria when the exosomes engulf by the recipient cells. In in vivo septic mouse model and in vitro cell model, it is shown that the exosome-based mitochondria delivery system delivers circRNA mSCAR into mitochondria preferentially in the macrophages, favoring macrophage polarization toward M2 subtype. Accordingly, the systemic inflammation is attenuated by exosome-based mitochondrial delivery of circRNA mSCAR, together with alleviated mortality. Collectively, the results uncover the critical role of circRNA mSCAR in sepsis, and provide a promising approach to attenuate sepsis via exosome-based mitochondrial delivery of circRNA mSCAR.

更新日期：2023-03-25

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