Liposomal Targeting Modifies Endosomal Escape: Design and Mechanistic Implications

Development of effective targeted nanoparticle (TNP) therapeutics requires rational design of targeted and endosomolytic moieties. Nevertheless, endosomal escape of TNPs is poorly understood, relying on extrapolation of knowledge from nontargeted (NP) systems. Here, we describe how incorporation of targeting elements on endosomolytic nanoparticles alters the endosomal escape mechanism. We demonstrated that NP and TNP systems react differently to addition of precise length oligohistidines and showcase the effects of alternating spatial arrangements of targeting and endosomolytic elements. The results established that these elements act cooperatively and must be incorporated as individual moieties, rather than a single multifunctional moiety, for optimal internalization by target cells.