Artificial Neutrophil-Mediated CEBPA-saRNA Delivery to Ameliorate ALI/ARDS

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