Harnessing the endosomal escape compartment as a strategy to enhance RNA delivery via lipid nanoparticles

Lipid nanoparticles (LNPs) have emerged as the leading platform for the delivery of RNA-based therapeutics.1 From the FDA approval of the first siRNA drug in 2018 (Onpattro) to the development of the first mRNA vaccines during the COVID-19 pandemic (Spikevax, Comirnaty), LNPs have overcome critical barriers to RNA delivery and accelerated the clinical translation of next-generation therapies. Yet, key challenges still hinder a global breakthrough in the market. At the systemic level, liver accumulation and off-target delivery represent fundamental issues; at the cellular level, endosomal escape remains a critical obstacle and has therefore been the focus of multiple publications in the field, including our recent review.