Lung Delivery of Self-Amplifying RNA: Finding a Balance Between Inflammation and Lasting Gene Activity

Intratracheal administration of optimized saRNA-lipid nanoparticles resulted in high levels of transgene expression in the lungs of mice for at least 21 days.

• Self-amplifying mRNA (saRNA) and lipid nanoparticles (LNPs) can activate the innate immune system, potentially complicating pulmonary delivery.
• Significant side effects linked to innate immune cell recruitment and cytokine release were observed following intratracheal administration of saRNA-LNPs.
• Systematic optimization of the LNP formulation and saRNA dose helped reduce lung inflammation to acceptable levels.
• Intratracheal delivery of optimized saRNA-LNPs encoding SARS-CoV-2 nanobodies led to detectable levels of nanobodies in the lungs.

Simplified