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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.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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