Charge-guided masking of a membrane-destabilizing peptide enables efficient endosomal escape for targeted intracellular delivery of proteins.

ABSTRACT: Intracellular delivery of biologicals such as peptides, proteins, and nucleic acids presents a great opportunity for innovative therapeutics. However, the endosome entrapment remains a major bottleneck in the intracellular delivery of biomacromolecules, largely limiting their therapeutic potential. Here, we converted a cell-penetrating peptide (CPP), low molecular weight protamine (LMWP), to endosomal escape peptides (EEPs) by masking LMWP with a pH-responsive counter-ionic peptide. The resulting masked CPPs (mLMWP and mLMWP2) effectively promoted the escape of peptide/protein cargoes from endosomes into the cytoplasm. Consequential lysosome repair and lysophagy were initiated upon the endolysosomal leakage. Minimal reactive oxygen species (ROS) elevation or cell death was observed. Based

SUBMITTER: Zhao Y 

PROVIDER: S-EPMC11544179 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature