There remains a striking overall mortality burden of COVID-19 worldwide. Given the waning effectiveness of current SARS-CoV-2 antivirals due to the rapid emergence of new variants of concern (VOC), we employed a direct-acting molecular therapy approach using gene silencing RNA interference (RNAi) technology. In this study, we developed and screened several ultra-conserved small-interfering RNAs (siRNAs) before selecting one potent siRNA candidate for pre-clinical testing. This non-immunostimulatory, anti-SARS-CoV-2 siRNA candidate maintains its antiviral activity against all tested SARS-CoV-2 VOC and works effectively as a single agent. For the first time, significant antiviral effects in both the lungs and nasal cavities of SARS-CoV-2 infected mice were observed when this siRNA candidate was delivered intranasally (IN) as a prophylactic agent with the aid of lipid nanoparticles (LNPs). Importantly, a pre-exposure prophylactic IN-delivered anti-SARS-CoV-2 siRNA antiviral that can ameliorate viral replication in the nasal cavity could potentially prevent aerosol spread of respiratory viruses. An IN delivery approach would allow for the development of a direct-acting nasal spray approach that could be self-administered prophylactically.

中文翻译：

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鼻内递送的超保守 siRNA 可预防性抑制肺和鼻腔中的 SARS-CoV-2 感染。

全球范围内，COVID-19 的总体死亡率负担依然惊人。鉴于新的关注变体 (VOC) 的迅速出现，当前 SARS-CoV-2 抗病毒药物的有效性逐渐减弱，我们采用了利用基因沉默 RNA 干扰 (RNAi) 技术的直接作用分子治疗方法。在这项研究中，我们开发并筛选了几种超保守的小干扰 RNA (siRNA)，然后选择一种有效的 siRNA 候选物进行临床前测试。这种非免疫刺激性抗 SARS-CoV-2 siRNA 候选药物对所有测试的 SARS-CoV-2 VOC 保持其抗病毒活性，并且作为单一药物有效发挥作用。当这种 siRNA 候选物在脂质纳米颗粒 (LNP) 的帮助下作为预防剂鼻内 (IN) 递送时，首次观察到对 SARS-CoV-2 感染小鼠的肺和鼻腔具有显着的抗病毒作用。重要的是，暴露前预防性 IN 递送的抗 SARS-CoV-2 siRNA 抗病毒药物可以改善鼻腔内的病毒复制，有可能防止呼吸道病毒的气溶胶传播。IN 给药方法将允许开发一种可以自我预防性给药的直接作用鼻喷雾方法。