{
  "abstract": "Wet age-related macular degeneration (AMD), a leading cause of irreversible vision loss, is driven by pathological choroidal neovascularization (CNV). Although anti-vascular endothelial growth factor (anti-VEGF) therapies remain the clinical standard, their utility is constrained by incomplete responses in nearly 50% of patients and off-target risks—such as geographic atrophy—stemming from non-specific VEGF blockade. Here, we identify a robust correlation between vascular cell adhesion molecule-1 (VCAM-1) and VEGF/VEGF receptor (VEGFR) expression in aqueous humor from AMD patients and in murine CNV models. Thus, we engineered a tetravalent bispecific protein, RHV, by functionalizing an L-rhamnulose-1-phosphate aldolase scaffold with peptides that selectively bind VCAM-1 and the VEGFR on neovessels. The tetravalent design confers high apparent affinity, enhancing pathological endothelial targeting while sparing healthy retinal vasculature. RHV induces concurrent internalization and lysosomal degradation of both VCAM-1 and VEGFR via a head-to-tail binding mode, leading to sustained inhibition of the VEGF/VEGFR, PI3K/AKT and Apelin/APJ signaling pathways. In murine CNV models, a single intravitreal injection of RHV exhibits superior ocular retention and lesion penetration, achieving therapeutic efficacy comparable to aflibercept [a ligand-trap fusion protein for VEGF-A, VEGF-B and placental growth factor (PIGF)] at one-quarter of the molar dose. This dual-receptor degradation-based strategy represents a targeted and durable approach for treating ocular neovascularization.",
  "abstract_shown": true,
  "affiliations": [
    "School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei 230026, China",
    "Key Laboratory of Nano-Bio Interface, Jiangsu Key Laboratory of Organoid Engineering and Precision Medicine, Division of Nanobiomedicine and i-Lab, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China",
    "Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou 21006, China",
    "School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China",
    "Global Institute of Future Technology, Shanghai Jiao Tong University, Shanghai 200240, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Jialun Zhang",
      "orcid": "0009-0003-9769-4204"
    },
    {
      "affs": [
        1
      ],
      "name": "Mingming Du"
    },
    {
      "affs": [
        2
      ],
      "name": "Lingying Ge",
      "orcid": "0009-0008-1660-7540"
    },
    {
      "affs": [
        1
      ],
      "name": "Yuheng Cao"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Jiang Jiang",
      "orcid": "0000-0003-2127-920X"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Xue Yin",
      "orcid": "0000-0001-7804-2065"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Guangcun Chen",
      "orcid": "0000-0002-6052-6632"
    },
    {
      "affs": [
        1,
        3,
        4
      ],
      "name": "Qiangbin Wang",
      "orcid": "0000-0001-6589-6328"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/d1pqx9dxk8x51.bib",
  "cited_by": 0,
  "doi": "10.1073/pnas.2613631123",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13752338/",
  "id": "d1pqx9dxk8x51",
  "issns": [
    "0027-8424",
    "1091-6490"
  ],
  "landing_url": "https://doi.org/10.1073/pnas.2613631123",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "409"
    ],
    [
      "heading",
      "410"
    ],
    [
      "heading",
      "Biological Sciences"
    ],
    [
      "heading",
      "Cell Biology"
    ],
    [
      "heading",
      "Chemistry"
    ],
    [
      "heading",
      "Physical Sciences"
    ],
    [
      "openalex",
      "2731|Retinal Diseases and Treatments"
    ]
  ],
  "openalex": "W7225273061",
  "pdf_url": null,
  "pmcid": "PMC13752338",
  "pmid": "42981038",
  "published": "2026-11-04",
  "publisher": "National Academy of Sciences",
  "ris": "https://research.draconitic.com/paper/d1pqx9dxk8x51.ris",
  "sources": [
    {
      "first_seen": "2026-11-15T12:21:45Z",
      "native_id": "PMC13752338",
      "source": "pmc",
      "url": "https://doi.org/10.1073/pnas.2613631123"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "heading:Cell Biology",
      "subfield": "cell-biology"
    },
    {
      "field": "chemistry",
      "origin": "heading:Chemistry",
      "subfield": "general"
    }
  ],
  "title": "A tetravalent bispecific protein enables targeted degradation of VCAM-1 and VEGFR for treatment of choroidal neovascularization",
  "title_text": "A tetravalent bispecific protein enables targeted degradation of VCAM-1 and VEGFR for treatment of choroidal neovascularization",
  "type": "peer-reviewed",
  "updated_at": "2026-11-15T12:21:45Z",
  "url": "https://research.draconitic.com/paper/d1pqx9dxk8x51",
  "venue": "Proceedings of the National Academy of Sciences of the United States of America",
  "versions": []
}