ABSTRACT Efficient oral delivery remains fundamentally constrained by harsh gastric milieu and intrinsic challenge of traversing multiple heterogeneous physiological barriers. Here, we elucidate that poly(lipoic acid)s (PLAs) holds great promise for oral delivery. Reversible thiol–disulfide exchange between PLAs and biological thiols at mucosal, epithelial and target cell interfaces drives traversal of each barrier, yielding 46% mucus permeability within 4 h, 26% epithelial transcytosis within 8 h, and high target‐cell penetration, all markedly reduced upon thiol blockade. Acid‐resistant yet neutral‐pH‐reactivatable thiol‐reactivity confers PLAs high gastric stability and efficient intestinal absorption for at least 12 h, while minimal epithelial and high target‐cell 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‐inflammatory and antioxidant protection to metabolically active organs. This well‐studied strategy is poised to offer insights for the future development of clinical oral therapeutics.
Zhang et al. (2026) studied this question.