Programmable Peptides Activated Macropinocytosis for Direct Cytosolic Delivery

Abstract

AbstractBioactive macromolecules show great promise for the treatment of various diseases. However, the cytosolic delivery of peptide‐based drugs remains a challenging task owing to the existence of multiple intracellular barriers and ineffective endosomal escape. To address these issues, herein, programmable self‐assembling peptide vectors are reported to amplify cargo internalization into the cytoplasm through receptor‐activated macropinocytosis. Programmable self‐assembling peptide vector‐active human epidermal growth factor receptor‐2 (HER2) signaling induces the receptor‐activated macropinocytosis pathway, achieving efficient uptake in tumor cells. Shrinking macropinosomes accelerate the process of assembly dynamics and form nanostructures in the cytoplasm to increase peptide‐based cargo accumulation and retention. Inductively coupled plasma mass (ICP‐MS) spectrometry quantitative analysis indicates that the Gd delivery efficiency in tumor tissue through the macropinocytosis pathway is improved 2.5‐fold compared with that through the use of active targeting molecular delivery. Finally, compared with nanoparticles and active targeting delivery, the delivery of bioactive peptide drugs through the self‐assembly of peptide vectors maintains high drug activity (the IC50 decreased twofold) in the cytoplasm and achieves effective inhibition of tumor cell growth. Programmable self‐assembling peptide vectors represent a promising platform for the intracellular delivery of diverse bioactive drugs, including molecular drugs, peptides, and biologics.