pH-sensitive endosomolytic peptides in gene and drug delivery: Endosomal escape and current challenges

Numerous endosomolytic agents have been developed to facilitate nanoparticle escape from the endosome and prevent destruction in the lysosome. Many endosomolytic agents are non-biodegradable, non-biocompatible, and exhibit a high level of cellular toxicity, limiting their use in gene/drug delivery systems. In recent years, pH-sensitive endosomolytic agents have been widely used in gene/drug delivery systems because they are biodegradable and biocompatible in nature. They are membrane inactive at neutral/physiological pH, but exhibit high toxicity at endosomal pH, allowing them to escape from the endosome to cytosol. We have discussed in detail the many forms of anionic and cationic pH-sensitive endosomolytic peptides (pSEPs) employed in gene/drug delivery for endosomal escape enhancement. Additionally, we explored in detail the several mechanisms by which pSEPs escape the endosome. Additionally, we reviewed in detail the creation of substantial helical structures at endosomal pH or in the presence of a membrane mimicking environment, as well as their relevance in promoting cargo endosomal escape.