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  3. A natural toolbox for brain delivery: Optimizing magnesium phosphate nanoparticles with "orifice-opening" compounds

A natural toolbox for brain delivery: Optimizing magnesium phosphate nanoparticles with "orifice-opening" compounds

  • Colloids Surf B Biointerfaces. 2026 Jun:262:115536. doi: 10.1016/j.colsurfb.2026.115536.
Jing Wang 1,  Chenghuan Song 2,  Zijie Wei 2,  Jiyun Shi 3,  Pingao Zhang 2,  Ting Yu 4,  Wanying Huang 2,  Lina Hou 2,  Rui Zhang 2,  Xiaoling Gao 2,  Xiaoli Yang 5,  Hao Wang 6,  Yongfang Zhang 7
Affiliations

Affiliations

  • 1 Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: [email protected].
  • 2 Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 3 Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Pharmacy, Affiliated Hospital of Jiangnan University, Wuxi 214000, China.
  • 4 Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Pharmacology, School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou 310053, China.
  • 5 Department of Neurology, Affiliated Hospital of Hebei University of Engineering, Handan 056002, China. Electronic address: [email protected].
  • 6 Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: [email protected].
  • 7 Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: [email protected].
PMID: 41678904 DOI: 10.1016/j.colsurfb.2026.115536
Abstract

The blood-brain barrier (BBB) imposes a severe constraint on the delivery of therapeutic agents for the treatment of brain disorders. In traditional Chinese medicine (TCM), "orifice-opening" compounds, including muscone (Mu), borneol (Bo), α-asarone (αA), and β-asarone (βA), are proposed to enhance the penetration of drugs into the brain. However, a systematic comparison of classic "orifice-opening" TCM agents and their underlying mechanisms remains unexplored. Herein, magnesium phosphate nanoparticles were employed to systematically compare the brain-targeting efficiency of these four "orifice-opening" compounds across both in vitro and in vivo experimental models. Our findings reveal a critical structure-activity dichotomy: free forms of Mu, Bo, and αA significantly enhanced brain targeting at optimal concentrations, primarily by regulating VEGF to disrupt BBB tight junctions. In contrast, βA was effective only when chemically conjugated to the nanoparticles. Mechanistic investigations uncovered that this conjugated βA promotes cellular uptake via multiple endocytic pathways (caveolin- and clathrin-mediated endocytosis, and macropinocytosis). Furthermore, it downregulated tight junction protein genes while upregulated Cytoskeleton and endocytosis-related pathways. These results highlight the influence of the application methods of the "orifice-opening" compounds on the brain-targeting effect of the nanoparticles. This strategy bridges ancient pharmacological concepts "orifice-opening" of TCM with modern nanotechnology, offering a promising platform for brain-targeted therapeutics.

Keywords

RNA-seq; blood-brain barrier; brain delivery; nanoparticles; natural product.

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