Issue 17, 2025

Histidine-rich enantiomeric peptide coacervates enhance antigen sequestration and presentation to T cells

Abstract

Peptides and peptidomimetics that self-assemble through LLPS have recently emerged as vital building blocks for creating functional biomaterials, thanks to their unique physicochemical properties and dynamic nature. One of life's most distinctive features is its selectivity for chiral molecules. To date, coacervates comprised of D-amino acids have not been reported. Here, we demonstrate that histidine-rich repeats of (GHGXY)4 (X = L/V/P) and their enantiomers undergo LLPS, paving the way for improved coacervate stability. Through a series of biophysical studies, we found that the droplet size can be tuned based on L, V, or P substitution, and molecular cargo between 600 and 150 000 Da is efficiently recruited in a bioactivity-preserving aqueous environment during phase separation. Mechanistic studies reveal that the droplets enter cells via energy-dependent endocytic pathways, exhibit composition-selective fusion properties, and effectively deliver molecular therapeutics across various cell types. Finally, we demonstrate that the coacervates enhance antigen presentation to CD4+ and CD8+ T cells, resulting in robust proliferation and the production of functional cytokines. Our study outlines the development and characterization of enantiomeric peptide coacervates as promising vaccine delivery vehicles with tunable physicochemical properties.

Graphical abstract: Histidine-rich enantiomeric peptide coacervates enhance antigen sequestration and presentation to T cells

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Article information

Article type
Edge Article
Submitted
13 Feb 2025
Accepted
24 Mar 2025
First published
25 Mar 2025
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2025,16, 7523-7536

Histidine-rich enantiomeric peptide coacervates enhance antigen sequestration and presentation to T cells

U. Pramanik, A. Das, E. M. Brown, H. L. Struckman, H. Wang, S. Stealey, M. L. Sprunger, A. Wasim, J. Fascetti, J. Mondal, J. R. Silva, S. P. Zustiak, M. E. Jackrel and J. S. Rudra, Chem. Sci., 2025, 16, 7523 DOI: 10.1039/D5SC01163A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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