Advancing endosomal escape of polymeric nanoparticles: towards improved intracellular delivery

Polymeric nanoparticles have emerged as a promising platform for the intracellular delivery of therapeutics, offering unique advantages such as tunable chemical properties and stimuli-responsive behavior. However, a significant challenge in their use remains the efficient delivery of therapeutic cargo to the site of action. This typically relies on escape from endosomal/lysosomal compartments where nanoparticles are trapped upon internalisation within a cell, a process termed endosomal escape. Despite considerable research, the mechanisms underlying endosomal escape are still poorly understood, with inconsistent findings across studies. Moreover, there is a notable lack of standardized methods to accurately quantify this escape process. In this review, we explore the current understanding of endosomal escape mechanisms specific to polymeric nanoparticles and explore critical design strategies that have been used. We also highlight recent advancements in methods to quantify endosomal escape, with the aim of promoting broader application of these technologies in understanding the behaviour of polymeric nanoparticles.