A novel dual-targeting strategy of nanobody-driven protein corona modulation for glioma therapy.

Yupei ZHANG; Shugang QIN; Tingting SONG; Zhiying HUANG; Zekai LV; Yang ZHAO; Xiangyu JIAO; Min SUN; Yinghan ZHANG; Guang XIE; Yuting CHEN; Xuli RUAN; Ruyue LIU; Haixing SHI; Chunli YANG; Siyu ZHAO; Zhongshan HE; Hai HUANG; Xiangrong SONG

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A novel dual-targeting strategy of nanobody-driven protein corona modulation for glioma therapy.

Author: Yupei ZHANG ¹ ; Shugang QIN ² ; Tingting SONG ¹ ; Zhiying HUANG ¹ ; Zekai LV ¹ ; Yang ZHAO ¹ ; Xiangyu JIAO ¹ ; Min SUN ¹ ; Yinghan ZHANG ¹ ; Guang XIE ¹ ; Yuting CHEN ¹ ; Xuli RUAN ¹ ; Ruyue LIU ¹ ; Haixing SHI ¹ ; Chunli YANG ¹ ; Siyu ZHAO ¹ ; Zhongshan HE ¹ ; Hai HUANG ¹ ; Xiangrong SONG ¹
Author Information

1. Department of Critical Care Medicine, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
2. Department of Experimental Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology, Chengdu 610040, China.
Publication Type:Journal Article
Keywords: BBB; Cisplatin; Dual-targeting; Glioma; Hitchhiking effect; Lipid nanoparticles; Nanobody; Protein coronas
From: Acta Pharmaceutica Sinica B 2025;15(9):4917-4931
CountryChina
Language:English
Abstract: Glioma represents the most prevalent malignant tumor of the central nervous system, with chemotherapy serving as an essential adjunctive treatment. However, most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier (BBB). This study introduced a novel dual-targeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles (C8Pt-Ls). Specifically, nanobodies (Nbs) with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls, resulting in the generation of Nb-C8Pt-Ls. Within the bloodstream, Nb-C8Pt-Ls could bound more fibrinogen, forming the protein corona that specifically interacted with LRP-1, a receptor highly expressed on the BBB. This interaction enabled a "Hitchhiking Effect" mechanism, facilitating efficient trans-BBB transport and promoting effective brain targeting. Additionally, the protein corona interacted with LRP-1, which is also overexpressed in glioma cells, achieving precise tumor targeting. Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1) complex, confirming its binding specificity and stability. Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors, induced apoptosis in glioma cells, and improved therapeutic efficacy. This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.