Regulation of cerebral blood flow boosts precise brain targeting of vinpocetine-derived ionizable-lipidoid nanoparticles

Xufei Bian, Ling Yang, Dingxi Jiang, Adam J. Grippin, Yifan Ma, Shuang Wu, Linchong Wu, Xiaoyou Wang, Zhongjie Tang, Kaicheng Tang, Weidong Pan, Shiyan Dong, Betty Y. S. Kim, Wen Jiang (), Zhaogang Yang () and Chong Li ()
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Xufei Bian: Southwest University
Ling Yang: Southwest University
Dingxi Jiang: Southwest University
Adam J. Grippin: The University of Texas MD Anderson Cancer Center
Yifan Ma: The University of Texas MD Anderson Cancer Center
Shuang Wu: Southwest University
Linchong Wu: Southwest University
Xiaoyou Wang: Southwest University
Zhongjie Tang: Southwest University
Kaicheng Tang: Southwest University
Weidong Pan: Guizhou University
Shiyan Dong: The University of Texas MD Anderson Cancer Center
Betty Y. S. Kim: The University of Texas MD Anderson Cancer Center
Wen Jiang: The University of Texas MD Anderson Cancer Center
Zhaogang Yang: Jilin University
Chong Li: Southwest University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Despite advances in active drug targeting for blood-brain barrier penetration, two key challenges persist: first, attachment of a targeting ligand to the drug or drug carrier does not enhance its brain biodistribution; and second, many brain diseases are intricately linked to microcirculation disorders that significantly impede drug accumulation within brain lesions even after they cross the barrier. Inspired by the neuroprotective properties of vinpocetine, which regulates cerebral blood flow, we propose a molecular library design centered on this class of cyclic tertiary amine compounds and develop a self-enhanced brain-targeted nucleic acid delivery system. Our findings reveal that: (i) vinpocetine-derived ionizable-lipidoid nanoparticles efficiently breach the blood-brain barrier; (ii) they have high gene-loading capacity, facilitating endosomal escape and intracellular transport; (iii) their administration is safe with minimal immunogenicity even with prolonged use; and (iv) they have potent pharmacologic brain-protective activity and may synergize with treatments for brain disorders as demonstrated in male APP/PS1 mice.

Date: 2024
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DOI: 10.1038/s41467-024-48461-4

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