siRNA Nanoparticle\nDry Powder Formulation with High\nTransfection Efficiency and Pulmonary Deposition for Acute Lung Injury\nTreatment

Acute lung injury (ALI) is a severe inflammatory syndrome,\nwhich\nwas caused by diverse factors. The COVID-19 pandemic has resulted\nin a higher mortality rate of these conditions. Currently, effective\ntreatments are lacking. Although siRNA nucleotide-based drugs are\npromising therapeutic approaches, their poor stability and inability\nto efficiently reach target cells limit their clinical translation.\nThis study identified a peptide from known cell-penetrating peptides\nthat can form an efficient anti-inflammatory complex with TNF-α\nsiRNA, termed SAR<sub>6</sub>EW/TNF-α siRNA. This complex can\neffectively transport TNF-α siRNA into the cytoplasm and achieve\npotent gene silencing in vitro as well as in vivo. By using lactose\nand triarginine as coexcipients and optimizing the spray-drying process,\na powder was produced with micrometer-scale spherical and porous structures,\nenhancing aerosol release and lung delivery efficiency. The dry powder\nformulation and process preserve the stability and integrity of the\nsiRNA. When administered intratracheally to ALI model mice, the complex\npowder demonstrated specific pulmonary gene silencing activity and\nsignificantly reduced inflammation symptoms caused by ALI, suggesting\na potential strategy for the clinical therapeutic approach of respiratory\ndiseases.