Inhibition of SARS-CoV-2 with short interfering RNA (siRNA) in a lung-on-a-chip model

LMU和KUM之间的这个合作项目的目的是优化抗病毒活性和短干扰RNA序列（sirna）的递送，以在人工肺模型中抑制冠状病毒。该方法的新颖之处在于siRNA序列及其递送的优化，病毒逃逸策略的评估，仿生肺模型（肺芯片）感染模型的建立，以及用于肺给药的RNA纳米制剂的雾化性研究。该项目的总体目标是更好地了解siRNA是否以及如何用于抑制肺部的冠状病毒，以进一步开发可吸入RNA疗法。本项目的创新核心包括以下几个要素：1。使用高活性siRNA序列，其靶区在不同冠状病毒物种中广泛保守。2. 优化siRNA序列及其递送以提高效率和降低免疫原性。3. 确定一种有效的策略来防止治疗中的病毒逃逸。4. 研究预防感染和感染后抑制病毒复制所需的RNA剂量和给药方案。5. 在微流控芯片（肺上芯片）上建立考虑肺环境的病毒感染模型。6. 用于肺给药的RNA纳米制剂的雾化性的研究。

The aim of this collaboration project between LMU and KUM is to optimize antiviral activity and delivery of short interfering RNA sequences (siRNAs) for coronavirus inhibition in an artificial lung model. The novelty of this approach consists in the optimization of the siRNA sequences and their delivery, in the assessment of strategies against viral escape, in the establishment of an infection model in a biomimetic lung model (lung-on-a-chip), and in the investigation of the aerosolizability of RNA nanoformulations for pulmonary dosing. The overarching goal of the project is to gain a better understanding of whether and how siRNA can be used to inhibit coronaviruses in the lungs for further development of inhalable RNA therapeutics. The innovative core of this project consists of the following elements: 1. The use of highly active siRNA sequences whose target regions are broadly conserved throughout different coronaviral species. 2. The optimization of siRNA sequences and their delivery for improved efficiency and reduced immunogenicity. 3. The identification of a potent strategy to prevent viral escape under therapy. 4. The investigation of necessary RNA doses and administration regimens for infection prevention as well as for inhibition of viral replication after infection. 5. The development of a virus infection model taking into account the lung environment on a microfluidic chip (lung-on-a-chip). 6. The investigation of the aersosolizability of the RNA nanoformulations for pulmonary dosing.