Self-assembled nanoaggregates in Wuzhuyu decoction: formation, absorption, transport, and alleviation of chronic migraine

Abstract

Self-assembled nanoaggregates (SANs) derived from herbal decoctions have emerged as promising natural nanomedicines. However, their formation patterns in multi-herb formulations and therapeutic roles in central nervous system disorders remain unclear. Wuzhuyu decoction (WZYD) is a classical formula for migraine treatment. Here, we reveal that SANs in WZYD (N-WZYDs) are formed through synergistic interactions among multiple herbal ingredients with Euodiae Fructus as the focus. N-WZYDs consisted mainly of proteoglycan scaffolds and small-molecule active components. In chronic migraine (CM) rat models, N-WZYDs significantly alleviated symptoms with efficacy comparable to that of WZYD, potentially via inhibition of the IL-33/ST2/TRPA1 signaling pathway. In Caco-2 cells, transport studies indicated that ginsenoside Rg₁, dehydroevodiamine, and rutaevin were poorly absorbed, whereas evodiamine and 6-gingerol were moderately absorbed but significantly active in efflux, indicating the intestine as a key site of action. As an oral medication, intact N-WZYDs accumulated primarily in the intestines and could be internalized by Caco-2 and enterochromaffin cells. Crucially, N-WZYDs promoted serotonin release from enterochromaffin cells more effectively than free active molecules alone and increased peripheral serotonin levels, thereby alleviating CM. By investigating the formation patterns, anti-CM mechanisms, and absorption behaviors of N-WZYDs, this study elucidated their material basis and brain−intestine interactions in treating CM, supporting their further development as therapeutic agents or drug delivery systems.

Keywords

Nanoaggregates / Wuzhuyu decoction / Chronic migraine / Self-assemble / Absorption / IL-33/ST2/TRPA1

Funding

This work was supported by the National Key R&D Program of China (No. 2023YFC3504000), the Beijing Natural Science Foundation–Capital Clinical Medicine Innovation Joint Fund (No. L2510038), the National Natural Science Foundation of China (No. 81473360), and the Beijing Pharmaceutical and Health Collaborative Initiative for High-Quality R&D of Traditional Chinese Medicine (No. zyygzl-2025-027).

Declaration of competing interest

These authors have no conflict of interest to declare.

Supporting information

Supporting information for this work can be obtained by contacting the corresponding authors via E-mail.

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