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Here, we elucidate that poly(lipoic acid)s (PLAs) holds great promise for oral delivery. Reversible thiol\u2013disulfide exchange between PLAs and biological thiols at mucosal, epithelial and target cell interfaces drives traversal of each barrier, yielding 46% mucus permeability within 4\u00a0h, 26% epithelial transcytosis within 8\u00a0h, and high target\u2010cell penetration, all markedly reduced upon thiol blockade. Acid\u2010resistant yet neutral\u2010pH\u2010reactivatable thiol\u2010reactivity confers PLAs high gastric stability and efficient intestinal absorption for at least 12\u00a0h, while minimal epithelial and high target\u2010cell degradation facilitate epithelial transcytosis and payload release at the site of action. Impressively, PLAs dramatically improves oral bioavailability of otherwise poorly absorbed clinical drugs, including small molecule paclitaxel (PTX@PLAs: 30%) and biologic cyclosporine A (CyA@PLAs: 52%), ranking among the most advanced systems in preclinical investigations. Moreover, PLAs exhibit highly biocompatible, as it degrades into natural antioxidant lipoic acid, which minimizes the metabolic risks while providing anti\u2010inflammatory and antioxidant protection to metabolically active organs. This well\u2010studied strategy is poised to offer insights for the future development of clinical oral therapeutics.<\/jats:p>","DOI":"10.1002\/smll.73970","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T15:16:36Z","timestamp":1780067796000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unraveling Oral Fate of Poly(Lipoic Acid)s: Mechanistic Insights and Delivery Horizons"],"prefix":"10.1002","volume":"22","author":[{"given":"Yi","family":"Zhang","sequence":"first","affiliation":[{"name":"National Engineering Research Center for Biomaterials and College of Biomedical Engineering Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Xiao","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for Biomaterials and College of Biomedical Engineering Sichuan University  Chengdu 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