Open AccessDynamic Continuum of Nanoscale Peptide Assemblies Facilitates Endocytosis and Endosomal Escape
Author(s) -
Hongjian He,
Jiaqi Guo,
Jiashu Xu,
Jiaqing Wang,
Shuang Liu,
Bing Xu
Publication year - 2021
Publication title -
nano letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.853
H-Index - 488
eISSN - 1530-6992
pISSN - 1530-6984
DOI - 10.1021/acs.nanolett.1c01029
Subject(s) - endocytosis , endosome , intracellular , biophysics , chemistry , lipid raft , caveolae , dephosphorylation , peptide , vesicle , microbiology and biotechnology , nanotechnology , phosphatase , membrane , phosphorylation , cell , materials science , biochemistry , biology
Alkaline phosphatase (ALP) enables intracellular targeting by peptide assemblies, but how the ALP substrates enter cells remains elusive. Here we show that nanoscale phosphopeptide assemblies cluster ALP to enable caveolae-mediated endocytosis (CME) and endosomal escape. Specifically, fluorescent phosphopeptides undergo enzyme-catalyzed self-assembly to form nanofibers. Live cell imaging unveils that phosphopeptides nanoparticles, coincubated with HEK293 cells overexpressing red fluorescent protein-tagged tissue-nonspecific ALP (TNAP-RFP), cluster TNAP-RFP in lipid rafts to enable CME. Further dephosphorylation of the phosphopeptides produces peptidic nanofibers for endosomal escape. Inhibiting TNAP, cleaving the membrane anchored TNAP, or disrupting lipid rafts abolishes the endocytosis. Decreasing the transformation to nanofibers prevents the endosomal escape. As the first study establishing a dynamic continuum of nanoscale assemblies for cellular uptake, this work illustrates an effective design for enzyme-responsive supramolecular therapeutics and provides mechanism insights for understanding the dynamics of cellular uptake of proteins or exogenous peptide aggregates.