Artificial Neutrophil-Mediated\nCEBPA-saRNA Delivery\nto Ameliorate ALI/ARDS

Acute lung injury/acute respiratory distress syndrome\n(ALI/ARDS)\nstill faces great challenges due to uncontrollable inflammation disorders,\ncomplicated causes of occurrence, and high mortality. Small-activating\nRNA (saRNA) has emerged as a novel and powerful gene-activating tool\nthat may be useful in the treatment of ALI/ARDS. However, effective\nsaRNA therapy is still challenged by the lack of effective and safe\ngene delivery vehicles. In this study, we develop a type of artificial\nneutrophil that is used to deliver saRNAs for ALI/ARDS treatment.\nThe saRNA targeting CCAAT-enhancer binding protein α (CEBPA-saRNA)\nis complexed with H1 histone and further camouflaged with neutrophil\nmembranes (NHR). Interestingly, we are the first to find that the\nH1 histone possesses the most effective binding capability to saRNA,\ncompared to other subtypes. The prepared NHR shows excellent physicochemical\nproperties, effective cellular uptake by the inflammatory M1 macrophages,\nand efficient activation of CEBPA, leading to significant M2 polarization.\nNHR shows an extended circulation lifetime and high-level accumulation\nin the inflamed lungs. The <i>in vivo</i> experiments indicate\nthat NHR ameliorates ALI in a mouse model. This type of artificial\nneutrophil shows powerful inflammatory inhibition both <i>in\nvitro</i> and <i>in vivo</i>, which opens a new avenue\nfor the treatment of ALI/ARDS.