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Herein, this work highlights the development of pH-triggered small molecule nanodrugs self-assembled from tryptamine (Try)-cinnamaldehyde (CA) and fisetin for targeted SAE therapy. The imine linkage in Try-CA and acid-dependent protonation of Try and fisetin endow the nanodrugs with pH-triggered dynamic changes of particle sizes, surficial charges, and drug release. Moreover, the combined use of Try-CA and fisetin also endows the nanodrugs with superior antioxidative, anti-inflammatory and antibacterial capabilities compared to their individual use. These characteristics of the nanodrugs facilitate long-term circulation stability, effective penetration through BBB, selective accumulation in the brain, and target to central and peripheral focal areas, thereby achieving comprehensive treatment or relief of SAE. Thus, these attractive experimental results illuminate the enormous potential of such pH-triggered small molecule nanodrugs for targeted SAE therapy, advancing their use in clinics.<\/jats:p>","DOI":"10.1177\/08853282251318052","type":"journal-article","created":{"date-parts":[[2025,2,2]],"date-time":"2025-02-02T20:19:52Z","timestamp":1738527592000},"page":"1165-1176","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["pH-triggered small molecule nanodrugs self-assembled from tryptamine-cinnamaldehyde and fisetin for targeted sepsis-associated encephalopathy therapy"],"prefix":"10.1177","volume":"39","author":[{"given":"Ximing","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, The Second Hospital of Anhui Medical University, Hefei, China"},{"name":"Department of Critical Care Medicine, First Affiliated Hospital of Bengbu Medical University, Bengbu, 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