Two Nature Biotechnology reports introduced orthogonal in vivo assays to quantify endosomal escape of lipid nanoparticles (LNPs), identifying lipid chemistries and formulations that improve cytosolic delivery of nucleic acid cargo in the liver. Teams used lysosomal barcoding and other barcoded reporter systems to measure which LNP designs permit RNA to escape endosomes and engage cellular machinery. The studies benchmarked branched ionizable lipids and mapped endosomal escape efficiency to therapeutic activity, offering a direct assay to guide LNP optimization for RNA therapeutics and gene editing. The methods enable head-to-head comparison of LNP libraries in living animals, accelerating translation of vaccines, mRNA therapeutics, and genome-editing payloads. Clarification: Endosomal escape is the step where internalized nanoparticles must breach endosomal membranes to release their RNA cargo into the cytosol—inefficient escape is a major barrier that reduces potency of LNP-delivered drugs.