Extracellular vesicle-encapsulated CC16 as novel nanotherapeutics for treatment of acute lung injury

Acute lung injury (ALI) is still associated with high mortality. Growing evidence suggests that Club Cell Protein 16 (CC16) plays a protective role against ALI. However, the doses of recom-binant CC16 (rCC16) used in preclinical studies are supraphy-siological for clinical applications. Extracellular vesicles (EVs) are nanovesicles endogenously generated by mammalian cells. Our study demonstrated that CC16 is released via small EVs and EV-encapsulated CC16 (sEV-CC16) and has anti-inflamma-tory activities, which protect mice from lipopolysaccharide (LPS) or bacteria-induced ALI. Additionally, sEV-CC16 can activate the DNA damage repair signaling pathways. Consistent with this activity, we observed more severe DNA damage in lungs from Cc16 knockout (KO) than wild-type (WT) mice. Mechanis-tically, we elucidated that CC16 suppresses nuclear factor KB (NF -KB) signaling activation by binding to heat shock protein 60 (HSP60). We concluded that sEV-CC16 could be a potential therapeutic agent for ALI by inhibiting the inflammatory and DNA damage responses by reducing NF -KB signaling.

Automated summary

The study reveals that CC16 released via small extracellular vesicles (sEVs) has anti-inflammatory activities and protects against ALI. sEV-encapsulated CC16 can activate DNA damage repair pathways and suppress NF-KB signaling by binding to HSP60. Therefore, sEV-CC16 could serve as a potential therapeutic agent for ALI by inhibiting inflammation and DNA damage responses.