Targeting RAGE with Nanobodies for Molecular Imaging of Cancers and Alzheimer's Disease

Guangfeng Liang; Fujing Wang; Wei Xiong; Guangwei Shi; Junling Yuan; Yang Li; Hongyan Zhang; Yanmei Xing; Shan Jin; Kongjun Yang; Zhongliang Dai; Jichao Sun; Zhijie Li; Jianhong Wang

doi:10.1002/adbi.202400617

Targeting RAGE with Nanobodies for Molecular Imaging of Cancers and Alzheimer's Disease

Adv Biol (Weinh). 2025 Jun 27:e00617. doi: 10.1002/adbi.202400617. Online ahead of print.

Authors

Guangfeng Liang¹, Fujing Wang^{2

3}, Wei Xiong^{2

4

5}, Guangwei Shi², Junling Yuan², Yang Li², Hongyan Zhang^{2

4}, Yanmei Xing^{2

4}, Shan Jin¹, Kongjun Yang¹, Zhongliang Dai^{2

4

5}, Jichao Sun², Zhijie Li^{2

6}, Jianhong Wang¹

Affiliations

¹ Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, 518118, China.
² Department of Geriatrics, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, China.
³ The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou, 510120, China.
⁴ Department of Anaesthesiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, China.
⁵ Department of Critical Care Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, China.
⁶ Department of Hyperbaric Oxygen Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, China.

PMID: 40579852
DOI: 10.1002/adbi.202400617

Abstract

The receptor for advanced glycation end products (RAGE) is a multifunctional cell surface receptor implicated in aging and the progression of chronic diseases, including cancer and Alzheimer's disease. Its interaction with advanced glycation end products (AGEs) promotes cellular stress and inflammation, underscoring the diagnostic and therapeutic relevance of targeting RAGE. In this study, we explored the potential of nanobodiessingle-domain antibodies known for high specificity, strong affinity, and deep tissue penetrationas molecular tools for RAGE-targeted applications. Using a phage display library, a panel of RAGE-specific nanobodies were isolated and characterized. Binding activity and affinity were evaluated through enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) assays. Among them, nanobody NbF8 demonstrated the highest affinity and specificity toward RAGE. In vitro, NbF8 selectively bound RAGE-expressing cells, while in vivo imaging in renal carcinoma and Alzheimer's disease mouse models confirmed its targeted accumulation in RAGE-overexpressing tumors and brain tissues. These findings highlight NbF8 as a promising molecular imaging agent for RAGE-associated diseases. This study supports the potential of RAGE-targeting nanobodies in both diagnostic imaging and therapeutic development, offering a novel approach for precision medicine in conditions driven by RAGE signaling.

Keywords: Alzheimer's disease; RAGE (Receptor for Advanced Glycation End Products); in vivo imaging; molecular diagnostics; nanobodies; renal carcinoma.

Abstract

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