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

• Published in: Advanced science 2023-05, Vol.10 (14), p.e2205692-n/a
• Main Authors: Fan, Li, Yao, Li, Li, Zhelong, Wan, Zhuo, Sun, Wenqi, Qiu, Shuo, Zhang, Wei, Xiao, Dan, Song, Liqiang, Yang, Guodong, Zhang, Yi, Wei, Mengying, Yang, Xuekang
• Format: Article
• Language: English
• Subjects: Animals; circRNA mSCAR; Cytokines; exosome; Exosomes - metabolism; Flow cytometry; Inflammation - metabolism; Macrophage Activation; macrophage polarization; Medical prognosis; Mice; MicroRNAs - genetics; Mitochondria; Mitochondrial DNA; mitochondrial targeted delivery; RNA, Circular - genetics; RNA, Circular - metabolism; Sepsis; Sepsis - therapy
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202205692

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. Exosomes encapsulated with circRNA mSCAR, a mitochondrial circRNA promoting M2 polarization via decreasing mitochondrial reactive oxygen species (mtROS), are additionally loaded with TPP‐PDL. Following in vivo delivery, circRNA mSCARs in the exosomes are preferentially delivered into the mitochondria of macrophage, promoting M2 macrophage polarization and thus attenuating sepsis.