Lipoproteins modulate the uptake and biological function of cationic cell-penetrating peptides across the animal lineage
Year: 2026
Type: preprint
Abstract: SUMMARY Cationic cell-penetrating peptides (+CPPs) are pervasive killer peptides produced by all animals and found in innate immune systems, venoms and neurodegenerative diseases. Despite their ubiquity, the mechanisms underlying their uptake remain opaque and intensely debated. Here, we interrogate +CPPs spanning 600 million years of animal evolution and identify endocytosis as a conserved/convergent uptake mechanism across cell types and organisms, at physiological concentrations. By combining multiplex imaging, genetic screening, cryo-electron tomography, and biophysical methods, we uncover that +CPPs seemingly universally enter eukaryote cells via “hitchhiking” on lipoproteins. We further show that the interaction of +CPPs with lipoproteins modulates their antimicrobial function. Combined, our findings establish a unified molecular framework describing a pan-eukaryote cell penetrance mechanism. As hyperlipidemia is a common comorbidity, our findings have direct implications for human health. Lastly, the insights gleaned from this work highlight design principles that may inform the future engineering of peptide-based therapeutics and delivery vehicles. eTOC BLURB Cationic cell-penetrating peptides are pervasive killer peptides in immunity, venoms and neurodegenerative disease, but their physiologically relevant molecular uptake mechanisms remain unresolved. Lipoprotein hitchhiking emerges as a conserved and convergent cell penetrance mechanism spanning the entire animal lineage and their protist pathogens, with direct implications to human health. HIGHLIGHTS Cationic cell-penetrating peptides are endocytosed across organisms and cell types. Endolysosomal uptake and escape constitute a functionally relevant entry route. Cationic peptides hitchhike on lipoprotein particles to gain cellular entry. Lipoproteins modulate the biological activity of cationic antimicrobial peptides.
Authors: Sovanny R. Taylor, Temilade V. Oluwasesin, Muthu Raj Salaikumaran, Borna Novak, Adam Briner, Roshan Ailani, Pilar I. Andrade, Paulo L. Onuchic, Olivia M. S. Carmo, Garam Kim, Jacob A. Blum, Mason Galliver, Catherine Stuart, Nicolas Mendez, Vedant Patel, Guo-Teng Liang, Ronan O’Connell, Mohammad Majharul Islam, Zeinab Kashaniasl, Maria Jose Villar, Yingqiong Cao, Xi-Lei Zeng, Lucas Porta, Haoyun Yang, Gabe Hohensee, Misha Kavalur, Rachel N. Arey, Sarah E. Blutt, Ewan K. S. McRae, Radbod Darabi, Lilei Zhang, Kathryn Jones, Simon G. Pfisterer, Chad Johnston, Jeroen Pollet, Mirian A. F. Hayashi, Aaron D. Gitler, Hyun-Kyoung Lee, Alex S. Holehouse, Steven J. Ludtke, Steven Boeynaems
Institutions: Baylor College of Medicine, Texas Children's Hospital, Washington University in St. Louis, The University of Queensland, Weizmann Institute of Science, Broad Institute, Stanford Medicine, Stanford University, University of Helsinki, University of Houston, Universidade Federal de São Paulo, Houston Methodist, Louisiana State University Health Sciences Center New Orleans, Cornell University, Weill Cornell Medicine, Chan Zuckerberg Biohub San Francisco, Dan L Duncan Comprehensive Cancer Center
Subfield: Microbiology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7204073325