Chemical synthesis of an atomically precise 2.5-MDa protein capsid and its mirror image
8 affiliations
- 1Department of Biochemistry and Molecular Biophysics
- 2University of California
- 3Cryo-EM facility
- 4Department of Chemistry and Biochemistry
- 5San Diego State University
- 6Department of Immunology and Microbiology
- 7The Scripps Research Institute
- 8Ionis Pharmaceuticals Inc.
Abstract
Protein capsids perform a broad range of biological functions 1–4 and can be engineered 5 as delivery vehicles, 6 nanoreactors, 7 biosensors, 8 and vaccines. 9 However, because the protein building blocks that make up these capsids must be expressed in biological systems, their composition is largely restricted to the canonical amino acids, limiting functionality. Assembling capsids from chemically synthesized proteins could circumvent this limitation but has not been accomplished due to a combination of technical challenges. Here we demonstrate the complete chemical synthesis of the 14.1-kDa coat protein of bacteriophage Qβ and its assembly into 180-subunit 2.5-MDa capsids. We exploit the expanded chemical palette afforded by total synthesis to produce mirror-image capsids composed entirely of unnatural D-amino acids. We determine the structures of the L- and D-capsids to 3-Å resolution by cryo-EM and verify their stereochemistry by cryo-ET. D-capsids elicit antibody titers 100-fold lower than their L-counterparts in mice, with the D-capsid response dominated by IgM antibodies. We demonstrate functional delivery in vivo using synthetic L-and D-capsids loaded with luciferase-encoding mRNA. By combining biological self-assembly with chemical synthesis, our results establish a route to producing a new class of programmable nanomaterials for diverse applications.
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BibTeX
@misc{harjung2026chemical,
title = {{Chemical synthesis of an atomically precise 2.5-MDa protein capsid and its mirror image}},
author = {Alexander Harjung and Chih-Chin Chi and Chuxuan Ling and Mariusz Matyszewski and Nino Makasarashvili and Lisa Kain and Kenna Nagy and Rui Huang and Matthew Campbell and Suyeong Han and Kira Podolsky and Inga Kuschnerus and Stormi Chadwick and Ember M. Tota and Payton Jensen and Moira A. McMahon and David J. Ecker and Luc Teyton and Rees F. Garmann and Neal K. Devaraj},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15009114/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009114/v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Chemical synthesis of an atomically precise 2.5-MDa protein capsid and its mirror image
AU - Alexander Harjung
AU - Chih-Chin Chi
AU - Chuxuan Ling
AU - Mariusz Matyszewski
AU - Nino Makasarashvili
AU - Lisa Kain
AU - Kenna Nagy
AU - Rui Huang
AU - Matthew Campbell
AU - Suyeong Han
AU - Kira Podolsky
AU - Inga Kuschnerus
AU - Stormi Chadwick
AU - Ember M. Tota
AU - Payton Jensen
AU - Moira A. McMahon
AU - David J. Ecker
AU - Luc Teyton
AU - Rees F. Garmann
AU - Neal K. Devaraj
PY - 2026
DA - 2026/09/20
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009114/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009114/v1
AB - Protein capsids perform a broad range of biological functions 1–4 and can be engineered 5 as delivery vehicles, 6 nanoreactors, 7 biosensors, 8 and vaccines. 9 However, because the protein building blocks that make up these capsids must be expressed in biological systems, their composition is largely restricted to the canonical amino acids, limiting functionality. Assembling capsids from chemically synthesized proteins could circumvent this limitation but has not been accomplished due to a combination of technical challenges. Here we demonstrate the complete chemical synthesis of the 14.1-kDa coat protein of bacteriophage Qβ and its assembly into 180-subunit 2.5-MDa capsids. We exploit the expanded chemical palette afforded by total synthesis to produce mirror-image capsids composed entirely of unnatural D-amino acids. We determine the structures of the L- and D-capsids to 3-Å resolution by cryo-EM and verify their stereochemistry by cryo-ET. D-capsids elicit antibody titers 100-fold lower than their L-counterparts in mice, with the D-capsid response dominated by IgM antibodies. We demonstrate functional delivery in vivo using synthetic L-and D-capsids loaded with luciferase-encoding mRNA. By combining biological self-assembly with chemical synthesis, our results establish a route to producing a new class of programmable nanomaterials for diverse applications.
ER -