A perspective on targeted LNPs.

Actively targeted lipid nanoparticles (tLNPs), in which LNPs are decorated with ligands for targeted delivery, offer a promising strategy to address a major challenge in nanomedicine: achieving efficient uptake in extrahepatic cells while limiting dominant uptake by the liver and unintended uptake by immune cells. tLNPs have now entered early clinical trials, with encouraging results reported for in vivo T-cell reprogramming. In this Perspective, we cover key considerations for the development of tLNP formulations. We discuss physicochemical factors related to ligand-PEG-lipid design and incorporation into LNPs, including ligand density, orientation, and localization, as well as extracellular and intracellular ligand-target engagement and safety considerations. We highlight recent early-stage clinical results in this area and preclinical applications in which tLNPs are currently being explored. Finally, we briefly highlight potential challenges associated with the reproducible and cost-effective manufacture of tLNPs and emphasize the need for additional analytical methods to adequately characterize these complex formulations.