{
  "abstract": "Glucose oxidase (GOx)-mediated glucose depletion is an attractive intervention strategy that can address the abnormal tumor metabolism characterized by elevated glycolysis. But its efficacy is limited by inefficient cellular delivery and hypoxia-induced stabilization of HIF-1α, which is associated with adaptive metabolic responses. Here, we report a chemically programmed albumin–GOx conjugate that couples microenvironment-responsive uptake with reductive release of acriflavine (ACF), a small molecule reported to interfere with HIF-1 signaling. Human serum albumin was used as the core carrier platform and engineered to include (1) dimethylmaleic anhydride groups to sense tumor-relevant acidic conditions and induce charge reversal for concomitant cellular delivery of both GOx and ACF payloads and (2) self-immolative disulfide linkage to release ACF under reductive conditions. The resulting GOx–albumin–ACF conjugate preserved GOx-mediated glucose oxidation and attenuated HIF-1α accumulation. Consequently, stronger metabolic disruption including suppressed lactate production and reduced adenosine triphosphate (ATP) levels was observed, together with enhanced cell death in two-dimensional cultures and three-dimensional tumor spheroids. By integrating chemical activation with modulation of the GOx-associated HIF-1α response, this work establishes a biomacromolecular design strategy for a protein-based, microenvironment-responsive therapeutic system that senses, responds, and acts within the tumor microenvironment to achieve enhanced metabolic disruption and cytotoxicity",
  "abstract_shown": true,
  "affiliations": [
    "Max Planck Institute for Polymer Research, Ackermannweg 10, Mainz, Germany, 55128",
    "Ulm University, Albert-Einstein-Allee 11, Ulm, Germany, 89081",
    "Institute of Immunology of the Research Center for Immunotherapy (FZI",
    "University Medical Center, Johannes Gutenberg University Mainz",
    "German Cancer Consortium (DKTK"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Lifan Hu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yulian Cheng"
    },
    {
      "affs": [
        0
      ],
      "name": "Jiyao Yu"
    },
    {
      "affs": [
        0
      ],
      "name": "Maria J. S. A. Silva"
    },
    {
      "affs": [
        0
      ],
      "name": "Lin Jian"
    },
    {
      "affs": [
        2,
        3,
        4
      ],
      "name": "Toszka Bohn"
    },
    {
      "affs": [
        0
      ],
      "name": "Kaloian Koynov"
    },
    {
      "affs": [
        0
      ],
      "name": "Seah Ling Kuan"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Tanja Weil",
      "orcid": "0000-0002-5906-7205"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cc01rx4f690n8.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15011191/v1",
  "fulltext_url": null,
  "id": "cc01rx4f690n8",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15011191/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",
      "1306|Cancer, Hypoxia, and Metabolism"
    ]
  ],
  "openalex": "W7224101035",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-28",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/cc01rx4f690n8.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:26Z",
      "native_id": "10.26434/chemrxiv.15011191",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15011191/v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:1306|Cancer, Hypoxia, and Metabolism",
      "subfield": "oncology"
    }
  ],
  "title": "Chemically Programmed Albumin–Enzyme Conjugates to Induce Microenvironment-Responsive Metabolic Disruption",
  "title_text": "Chemically Programmed Albumin–Enzyme Conjugates to Induce Microenvironment-Responsive Metabolic Disruption",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:26Z",
  "url": "https://research.draconitic.com/paper/cc01rx4f690n8",
  "venue": "ChemRxiv",
  "versions": []
}