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<p>Despite advances in vaccine and antiviral drug development, the prevention of respiratory viral infection and transmission remains a substantial challenge worldwide. One obvious limitation of these approaches is that they do not provide robust protection at the initial site of infection, which is the respiratory mucosa. Currently, strategies to enhance mucosal immunity against respiratory pathogens remain lacking. Here we engineered mucus-tethering bispecific nanobodies designed to provide the simultaneous neutralization of viruses by binding to their surface proteins and the entrapment of viruses within the mucus by securing them to mucin. Compared with conventional non-mucus-tethering nanobodies, these mucus-tethering bispecific nanobodies demonstrated increased retention in the respiratory tract, provided enhanced protection against influenza viral infection in mice and reduced SARS-CoV-2 transmission in hamsters. Together, our findings represent a promising strategy for enhancing mucosal defences against respiratory viruses by blocking viral entry and limiting onward transmission.</p>

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Engineered mucus-tethering bispecific nanobodies enhance mucosal immunity against respiratory pathogens

  • 期刊论文

  • 发表日期：

    2026年1月21日

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  • Liming Zhao,
  • Kyle L. O’Donnell,
  • Megha Dubey,
  • Yuting Wang,
  • Nathan R. Martinez,
  • Yunxiao Zhang,
  • Holly M. Steininger,
  • Chao Ma,
  • Vamsee Mallajosyula,
  • Lorene L. Y. Lee,
  • Rovin N. Lachmansingh,
  • Suzan Stavitsky,
  • Eri Takematsu,
  • Malachia Y. Hoover,
  • Honglin Chen,
  • Jing Guo,
  • Annette Wu,
  • Yifan Ma,
  • Xiaotian Wang,
  • Ansel P. Nalin,
  • Seong Dong Jeong,
  • Wan-Jin Lu,
  • Patricia K. Nguyen,
  • Chad S. Clancy,
  • Michal C. Tal,
  • Jun Xiao,
  • Michael T. Longaker,
  • Andrew S. Lee,
  • Betty Y. S. Kim,
  • Thomas H. Ambrosi,
  • Irving L. Weissman,
  • Mark M. Davis,
  • Kim J. Hasenkrug,
  • Yueh-hsiu Chien,
  • Wen Jiang,
  • Andrea Marzi,
  • Charles K. F. Chan

摘要

Despite advances in vaccine and antiviral drug development, the prevention of respiratory viral infection and transmission remains a substantial challenge worldwide. One obvious limitation of these approaches is that they do not provide robust protection at the initial site of infection, which is the respiratory mucosa. Currently, strategies to enhance mucosal immunity against respiratory pathogens remain lacking. Here we engineered mucus-tethering bispecific nanobodies designed to provide the simultaneous neutralization of viruses by binding to their surface proteins and the entrapment of viruses within the mucus by securing them to mucin. Compared with conventional non-mucus-tethering nanobodies, these mucus-tethering bispecific nanobodies demonstrated increased retention in the respiratory tract, provided enhanced protection against influenza viral infection in mice and reduced SARS-CoV-2 transmission in hamsters. Together, our findings represent a promising strategy for enhancing mucosal defences against respiratory viruses by blocking viral entry and limiting onward transmission.