{
  "abstract": "Lipid nanoparticle delivery of mRNA enables in vivo generation of CAR-T cells while avoiding viral vector manufacturing constraints. However, transient expression places stringent requirements on the developability of CAR components, particularly single-chain variable fragments (scFvs). Here we examine how intrinsic scFv biophysical quality governs CAR expression and function under mRNA delivery. Using a humanisation and optimisation workflow guided by computational developability metrics, we engineered scFv variants from three clinically relevant antibody families (FMC63, 14G2a and MGA271/chBRCA84D) spanning a range of baseline stability and aggregation propensity. Optimised variants showed increased humanness and, in most cases, improved thermal stability and reduced non-specific interactions while broadly preserving antigen recognition. Functional testing in primary human T cells following mRNA–LNP delivery revealed strong dependence on starting binder quality: optimisation produced minimal functional change for the stable, predominantly monomeric FMC63 scFv, whereas stabilisation of the aggregation-prone 14G2a scFv markedly increased CAR surface expression and cytotoxic activity. For MGA271-derived binders, optimisation reduced non-specific interactions and off-target killing despite reduced monovalent affinity. Together, these data establish developability engineering of scFvs as a critical enabling step for transient mRNA-encoded CAR therapies.",
  "abstract_shown": true,
  "affiliations": [
    "Chimeris UK",
    "Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Maurizio Mangolini"
    },
    {
      "affs": [
        1
      ],
      "name": "Aubin Ramon"
    },
    {
      "affs": [
        1
      ],
      "name": "Bingqian Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Emily Souster"
    },
    {
      "affs": [
        0
      ],
      "name": "Jasvinder Hayre"
    },
    {
      "affs": [
        0
      ],
      "name": "Rajesh Karattil"
    },
    {
      "affs": [
        1
      ],
      "name": "Pietro Sormanni"
    },
    {
      "affs": [
        0
      ],
      "name": "Shimobi Onuoha"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fr9q2t3xbqmbw.bib",
  "cited_by": 1,
  "doi": "10.1038/s41598-026-60295-2",
  "fulltext_url": "https://doi.org/10.1038/s41598-026-60295-2",
  "id": "fr9q2t3xbqmbw",
  "issns": [
    "2045-2322"
  ],
  "landing_url": "https://doi.org/10.1038/s41598-026-60295-2",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "Q"
    ],
    [
      "lcc",
      "R"
    ],
    [
      "openalex",
      "2730|CAR-T cell therapy research"
    ]
  ],
  "openalex": "W7169671968",
  "pdf_url": "https://www.nature.com/articles/s41598-026-60295-2_reference.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-07-01",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/fr9q2t3xbqmbw.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:45:58Z",
      "native_id": "a46c96b35e75466c88ff299933201f7a",
      "source": "doaj",
      "url": "https://doi.org/10.1038/s41598-026-60295-2"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|CAR-T cell therapy research",
      "subfield": "oncology"
    }
  ],
  "title": "Developability engineering of scFvs enables robust CAR function under transient mRNA expression",
  "title_text": "Developability engineering of scFvs enables robust CAR function under transient mRNA expression",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:45:58Z",
  "url": "https://research.draconitic.com/paper/fr9q2t3xbqmbw",
  "venue": "Scientific Reports",
  "versions": []
}