{
  "abstract": "As complex biotherapeutics continue to evolve, the demand for single-site, multi-functionalized protein conjugates intensifies. Current methods often suffer from maleimide-related hydrolytic instability or require multi-step invasive protein modifications. Here, we establish 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones (5HP2O) as modular, hydrolytically stable hubs for assembling multi-functional protein-oligonucleotide conjugates (POCs). Synthesized via one-pot photooxidation of 2-substituted furans, these linkers incorporate tunable spacers, 5HP2O Michael acceptor, a NHS active ester and secondary cargoes. We demonstrate that 5HP2O-functionalized amino-oligonucleotides (AON) maintain complete hydrolytic resistance across a broad pH range, streamlining intermediate storage. Subsequent bioconjugation yields constructs with superior retro-Michael stability compared to aliphatic maleimide analogues. Expanding this platform, we generated diverse heterobifunctional, trifunctional (click-reactive and fluorescent), and tetrafunctional (enzymatically cleavable) linkers. We validated these tools through in vitro conjugate tracking and the assembly of a dual-antisense oligonucleotide conjugate.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "name": "Jan H. Meffert",
      "orcid": "0000-0003-4342-5618"
    },
    {
      "name": "Alexandros Kostakis"
    },
    {
      "name": "Joshua McHale",
      "orcid": "0000-0003-0435-7122"
    },
    {
      "name": "Sara Mangsbo"
    },
    {
      "name": "Carlo Vascotto"
    },
    {
      "name": "Martin Bollmark",
      "orcid": "0000-0002-3715-1959"
    },
    {
      "name": "Annemieke Madder",
      "orcid": "0000-0003-0179-7608"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bg8p5qevedz12.bib",
  "cited_by": 0,
  "doi": "10.1038/s42004-026-02238-6",
  "fulltext_url": null,
  "id": "bg8p5qevedz12",
  "issns": [
    "2399-3669"
  ],
  "landing_url": "https://www.nature.com/articles/s42004-026-02238-6",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|DNA and Nucleic Acid Chemistry"
    ]
  ],
  "openalex": "W7221312855",
  "pdf_url": "https://www.nature.com/articles/s42004-026-02238-6_reference.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-10",
  "publisher": "Springer Science and Business Media LLC",
  "ris": "https://research.draconitic.com/paper/bg8p5qevedz12.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:51Z",
      "native_id": "10.1038/s42004-026-02238-6",
      "source": "crossref",
      "url": "https://www.nature.com/articles/s42004-026-02238-6"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|DNA and Nucleic Acid Chemistry",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Modular multifunctional 5HP2O linkers for the versatile assembly of protein-oligonucleotide conjugates",
  "title_text": "Modular multifunctional 5HP2O linkers for the versatile assembly of protein-oligonucleotide conjugates",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:51Z",
  "url": "https://research.draconitic.com/paper/bg8p5qevedz12",
  "venue": "Communications Chemistry",
  "versions": []
}