Chang, Yi-ChungYi-ChungChangChen, Yi-FenYi-FenChenYang, Chi-FanChi-FanYangHo, Hui-JuHui-JuHoYang, Jen FuJen FuYangChou, Yuan-LinYuan-LinChouLin, Ching-WenChing-WenLinPAN-CHYR YANG2025-05-142025-05-142025-03https://scholars.lib.ntu.edu.tw/handle/123456789/729284Severe acute respiratory syndrome caused by the coronavirus (SARS-CoV-2) in the COVID-19 pandemic has highlighted the need for effective treatments, as rapid viral mutations complicate therapeutic development. SNS812, a fully modified inhaled siRNA that targets the conserved RNA-dependent RNA polymerase (RdRP) gene of SARS-CoV-2, has been shown to possess its suppression ability against wide-spectrum SARS-COV-2 variants preclinically. To evaluate the safety and tolerability of inhaled SNS812 in healthy participants, a randomized, double-blind, placebo-controlled phase 1 trial was conducted. To justify the first-in-human inhalation study, this research was divided into two parts: single ascending doses (0.3, 0.6, and 1.2 mg/kg) and multiple doses (0.6 and 1.2 mg/kg) of daily inhalation for seven consecutive days to assess the safety, tolerability, immunogenicity, and pharmacokinetics of SNS812. Of the 44 participants, 3 in the 0.3 mg/kg single-dose group, 2 in the 1.2 mg/kg multiple ascending doses group, and 1 in the placebo group reported treatment-emergent adverse events (TEAEs). No serious adverse events (SAEs), treatment-related adverse events (TRAEs), or TEAEs caused discontinuation or deaths were observed. PK showed rapid absorption of SNS812, with peak concentrations (median T) reached at 1.5-2 h, and an elimination half-life (t ) between 4.96 and 7.08 h. No antidrug antibodies (ADAs) were detected in either group. The results demonstrated that the first-in-human, fully modified with wide-spectrum anti-SARS-COV2 siRNA by inhalation following a single dose and multiple doses was safe and well tolerated in healthy participants. Trial Registration: NCT05677893.enSARS‐COV2nasal spraysiRNAsjournal article10.1111/cts.7020240116355