Targeting and tracking mRNA lipid nanoparticles at the particle, transcript and protein level

Lipid nanoparticles (LNPs) are a versatile platform with numerous experimental, diagnostic and therapeutic applications. However, the high propensity of LNPs to accumulate in hepatocytes and antigen-presenting cells has largely limited their clinical use to vaccines and the treatment of liver diseases. In this Review, we describe established and emerging techniques for monitoring the in vivo behaviour of RNA-loaded LNPs (RNA-LNPs) and strategies for improved tissue and cell targeting that expand the applications of this technology. We discuss innovations in LNP chemistry and bioengineering, and exploiting synthetic biology to tailor the cellular expression of the mRNA cargo, including the use of microRNA target sites. We also review how modifications to the encoded protein can be used to control stability and subcellular localization of the payload. Lastly, we discuss how these techniques and strategies can accelerate the clinical translation of RNA-LNP drugs and improve therapeutic outcomes. This Review explores strategies for targeting and tracking RNA-LNP drugs, monitoring their in vivo behaviour, enhancing tissue-specific delivery, and using synthetic biology to control mRNA expression and protein localization.