Extracellular nanobodies for GPCR modulation mechanisms, engineering, and therapeutic possibilities

Yuchen Xiao; Zhuoqun Liu; Jiqing Xie; Zhiran Fan; Tianjun Wang; David J.H. Shih; Shikang Liang; Honglei Tian; Liu Liu; Wensen Cao; Feng Tian; Jianjun Lyu; Lingjing Jin; Chao Zhang

doi:10.59717/j.xinn-life.2026.100176

The Innovation Life > 2026 Vol. 4 > No. 2 > 100176

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Extracellular nanobodies for GPCR modulation mechanisms, engineering, and therapeutic possibilities

1.
Fundamental Research Center, Shanghai Yangzhi Rehabilitation Hospital, School of Medicine, Tongji University, Shanghai 201619, China
2.
Pharmacy Department of Medical Security Center of the 960th Hospital of Joint Service Support Force of Chinese PLA, Jinan 250031, China
3.
Wuhan Nano Body Life Science and Technology Co., Ltd, East Lake New Technology Development Zone, Wuhan 430075, China
4.
Hebei General Hospital, No. 348 Heping West Road, Xinhua District, Shijiazhuang 050051, China
5.
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR 999077, China
6.
Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR 999077, China
7.
Shanghai Yuhui Pharmaceutical Technology (Group) Co., Ltd., Shanghai 201203, China
8.
Guanghua Academy, No.2790, Chuanzhou Road, Shanghai 201319, China
9.
Hebei Key Laboratory of Medical Data Science, Institute of Biomedical Informatics, School of Medicine, Hebei University of Engineering, Handan 056038, China
10.
Hubei Topgene Research Institute of Hubei Topgene Biotechnology Group Co., Ltd., East Lake High-Tech Development Zone, Wuhan 430205, China
11.
Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
12.
These authors contributed equally

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Corresponding authors: tianfeng@hebeu.edu.cn (F.T.); lvjianjun@topgenebio.com (J.L.); lingjingjin@tongji.edu.cn (L.J.); zhangchao@shsmu.edu.cn (C.Z.)
Received Date: October 24, 2025

Accepted Date: March 23, 2026

Published Online: April 07, 2026

The Innovation Life 4(2), https://doi.org/10.59717/j.xinn-life.2026.100176 | Cite this article

GRAPHICAL ABSTRACT

GRAPHICAL ABSTRACT

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PUBLIC SUMMARY

PUBLIC SUMMARY
1. Nanobodies (single-domain antibodies) target G protein-coupled receptors (GPCRs)，including orphan GPCRs.
  
  Nanobodies act as antagonists, agonists, or allosteric modulators to control GPCR signaling.
  
  Nanobodies improve precision and safety in treating diseases like cancer and neurological disorders.
  
  Nanobody engineering and AI-based design enhance drug targeting and therapeutic efficacy.

ABSTRACT

ABSTRACT

GPCRs act as the core of cell signaling and play crucial roles in the development and progression of major diseases, including cancer, neurological disorders, and metabolic diseases. Nanobodies are single-domain antibodies originally derived from camelids. They are small in size, easy to design, highly penetrable, with a high affinity, and have become an ideal tool for controlling GPCR signaling. Nanobodies can act as agonists, antagonists or positive/negative allosteric regulators by recognizing the extracellular loops (ECLs), ligand-binding sites, or allosteric sites of GPCRs, stabilizing specific conformations and inducing biased signaling, which can significantly improve the precision of regulation and the therapeutic window. In this article, we summarize the action of nanobodies in regulating GPCRs: extracellular and intracellular targeting, ligand site blockade, biasd signaling regulation, structure-directed functional modification, and antagonistic properties of novel target GPCRs, such as CXCR4/CXCR7, APJ, and MC4R. We evaluate their potential applications and advantages in viral GPCRs, peptide-like receptors, and angiotensin receptors, among others. We also discuss the cutting-edge applications of nanobodies in orphan GPCR targeting, heterodimer modulation, transmembrane transport (e.g., crossing the blood-brain barrier), and their potentials in difficult-to-formulate GPCRs. In the future, along with AI-based structure prediction and high-throughput screening platforms, nanobodies will be able to evolve intelligently from function definition to precise construction. Especially in the context of bispecific and multivalent constructs as well as nano-delivery systems, nanobodies will be the engine of GPCR regulation strategies to provide safer, more specific, and efficient treatments for refractory neurological, metabolic, and tumor diseases.

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Xiao Y., Liu Z., Xie J., et al. (2026). Extracellular nanobodies for GPCR modulation mechanisms, engineering, and therapeutic possibilities. The Innovation Life 4:100176. https://doi.org/10.59717/j.xinn-life.2026.100176

Xiao Y., Liu Z., Xie J., et al. (2026). Extracellular nanobodies for GPCR modulation mechanisms, engineering, and therapeutic possibilities. The Innovation Life 4:100176. https://doi.org/10.59717/j.xinn-life.2026.100176

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Extracellular nanobodies for GPCR modulation mechanisms, engineering, and therapeutic possibilities

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