The Biology of Endosomal Escape: Strategies for Enhanced Delivery of Therapeutics.

Intracellular delivery of biomolecules is essential to the success of modern therapeutics, yet endosomal entrapment remains a critical barrier to efficacy, and this has been highlighted with the push toward lipid nanoparticle (LNP) therapeutic delivery. Following cellular uptake, most cargo becomes sequestered in endosomes, where it is vulnerable to degradation or exocytosis, unless effective escape mechanisms are triggered. Here, we examine how the efficiency of cellular uptake and the ability to breach endosomal membranes jointly determine the bioavailability and functional delivery of therapeutic agents. We explore natural strategies evolved by pathogens, including membrane fusion, pore formation, and lipid remodeling, as well as emerging technologies to harness this knowledge to enhance delivery of therapeutic cargo to the cytoplasm. By bridging cellular biology with translational design, this review highlights the combined importance of sufficient uptake and effective escape in optimizing cargo delivery and outlines current innovations aimed at overcoming this long-standing bottleneck.