{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biochemistry and Molecular Biophysics",
    "University of California",
    "Cryo-EM facility",
    "Department of Chemistry and Biochemistry",
    "San Diego State University",
    "Department of Immunology and Microbiology",
    "The Scripps Research Institute",
    "Ionis Pharmaceuticals Inc."
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 20,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Alexander Harjung",
      "orcid": "0009-0002-4219-4686"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Chih-Chin Chi"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Chuxuan Ling"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Mariusz Matyszewski"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Nino Makasarashvili"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Lisa Kain"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Kenna Nagy"
    },
    {
      "affs": [
        7
      ],
      "name": "Rui Huang"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Matthew Campbell"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Suyeong Han"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Kira Podolsky"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Inga Kuschnerus"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Stormi Chadwick"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Ember M. Tota"
    },
    {
      "affs": [
        7
      ],
      "name": "Payton Jensen"
    },
    {
      "affs": [
        7
      ],
      "name": "Moira A. McMahon"
    },
    {
      "affs": [
        7
      ],
      "name": "David J. Ecker"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Luc Teyton"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Rees F. Garmann"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Neal K. Devaraj"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4dj3jz48cnw8g.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15009114/v1",
  "fulltext_url": null,
  "id": "4dj3jz48cnw8g",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009114/v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Chemical Synthesis and Analysis"
    ]
  ],
  "openalex": "W7213917454",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15009114/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-20",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/4dj3jz48cnw8g.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:19Z",
      "native_id": "10.26434/chemrxiv.15009114",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009114/v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Chemical Synthesis and Analysis",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Chemical synthesis of an atomically precise 2.5-MDa protein capsid and its mirror image",
  "title_text": "Chemical synthesis of an atomically precise 2.5-MDa protein capsid and its mirror image",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:19Z",
  "url": "https://research.draconitic.com/paper/4dj3jz48cnw8g",
  "venue": "ChemRxiv",
  "versions": []
}