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Topical delivery of a human single-domain antibody targeting IL-33 to inhibit mucosal inflammation

Cellular & Molecular Immunology volume 22, pages 918–934 (2025)Cite this article

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Abstract

Addressing mucosal inflammatory disorders in the ocular surface or respiratory system remains a formidable challenge owing to the limited penetration of biological therapeutics across epithelial barriers. In this study, we explored the potential of human single-domain antibodies (UdAbs) as topical therapeutics for the targeted modulation of interleukin-33 (IL-33) in two mucosal-associated inflammatory disorders. The anti-IL-33 UdAb A12 demonstrated potent inhibition of the IL-33-mediated signaling pathway, despite not potently blocking the IL-33 receptor interaction. Compared with the anti-IL-33 control IgG itepekimab, the topical delivery of A12 resulted in significantly elevated corneal concentrations in vivo, which resulted in negligible ocular penetration. Moreover, A12 considerably ameliorated dry eye disease severity by exerting anti-inflammatory effects. Furthermore, in another murine model of allergic asthma, inhaled A12 substantially reduced overall lung inflammation. Our findings revealed the capacity of UdAbs to penetrate mucosal barriers following noninvasive localized delivery, highlighting their potential as an innovative therapeutic strategy for modulating mucosal inflammation.

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Acknowledgements

TY and YLW are supported by grants from the National Natural Science Foundation of China (82394450, 92459301, 32270984), the Science and Technology Commission of Shanghai Municipality (23XD1400800), the Shanghai Municipal Health Commission (GWVI-11.2-YQ46), and the Fund of Fudan University and Cao’ejiang Basic Research (24FCB09). JH is supported by the National Science Fund for Distinguished Young Scholars (82425015), the National Natural Science Foundation of China (82171102), the National Key Research and Development Program of China (2023YFA0915003), the Shanghai Medical Innovation Research Program (22Y21900900), the “Dawn” Program of the Shanghai Municipal Education Commission (24SG11), the Shanghai Science and Technology Innovation Action Plan for Cell and Gene Therapy (24J22800500), the Shanghai Science and Technology Innovation Action Plan for Advanced Materials (24CL2900802), the Shanghai Municipal Commission of Health (20254Z0019), and the Shanghai Medicine and Health Development Foundation.

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  1. These authors contributed equally: Keke Huang, Yuqing Wu.

Authors and Affiliations

  1. MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Institute of Infectious Disease and Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China

    Keke Huang, Yu Kong, Mingwei Lv, Quanxiao Li, Cheng Li, Wenping Song, Xiaoyi Zhu, Tianlei Ying & Yanling Wu

  2. Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, Fudan University, Shanghai, China

    Yuqing Wu, Yirou Zhang, Yiteng Lu, Changchang Xin, Xujiao Zhou & Jiaxu Hong

  3. NHC Key laboratory of Myopia and Related Eye Diseases Shanghai, Shanghai, China

    Yuqing Wu, Yirou Zhang, Yiteng Lu, Changchang Xin, Xujiao Zhou & Jiaxu Hong

  4. Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China

    Qingyuan Xu & Zhenlin Yang

  5. Shanghai Engineering Research Center for Synthetic Immunology, Shanghai, China

    Tianlei Ying, Yanling Wu & Jiaxu Hong

  6. Shanghai Key Laboratory of Rare Disease Gene Editing and Cell Therapy, Shanghai, China

    Jiaxu Hong

  7. Department of Ophthalmology, Children’s Hospital of Fudan University, National Pediatric Medical Center of China, Shanghai, China

    Jiaxu Hong

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Contributions

JH, YLW and TY initiated, planned and supervised the project. KH and YQW performed most of the experiments and analyzed the data with assistance from YK, QX, ML, YZ, YL, QL, CL, WS and XZ. The manuscript was reviewed, commented upon and approved by all the authors.

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Correspondence to Tianlei Ying, Yanling Wu or Jiaxu Hong.

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JH, YLW, and KH are listed as inventors on one patent application related to this work. The authors declare that they have no competing interests.

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Huang, K., Wu, Y., Kong, Y. et al. Topical delivery of a human single-domain antibody targeting IL-33 to inhibit mucosal inflammation. Cell Mol Immunol 22, 918–934 (2025). https://doi.org/10.1038/s41423-025-01305-7

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