Abstract / Summary
Abstract Esophageal adenocarcinoma (EAC) is an aggressive malignancy characterized by severe therapeutic resistance and a dismal prognosis. Although the green tea polyphenol epigallocatechin-3-gallate (EGCG) possesses potent anti-cancer properties, its clinical translation is restricted by poor stability and low bioavailability. To overcome these bottlenecks, we engineered a biocompatible nanoplatform utilizing bovine milk exosomes to encapsulate EGCG (Exo-EGCG). The resulting formulations exhibited favorable physicochemical attributes, including an average hydrodynamic diameter of 130.6 ± 3.6 nm, excellent colloidal stability, high encapsulation efficiency (78.5 ± 5.6%), and a sustained, pH-responsive biphasic release profile accelerated at pH 5.5. In vitro screens against human EAC lines (SKGT-4 and FLO-1) demonstrated that exosomal encapsulation drastically enhanced the anti-proliferative and anti-clonogenic performance of EGCG. MTT profiling revealed time- and dose-dependent reductions in IC 50 values, driven by enhanced exsomes mediated endocytosis. Furthermore, Exo-EGCG triggered a catastrophic intracellular oxidative burst, characterized by a significant ( p < 0.05) upsurge in global cytoplasmic reactive oxygen species (ROS) and localized mitochondrial superoxide overproduction, effectively crippling the mitochondrial network. Furthermore, sub-toxic concentrations (15 µM) of Exo-EGCG markedly suppressed lateral and transwell cell migration by attenuating essential pro-metastatic drivers. FLO-1 cells exhibited more rapid baseline migration and higher susceptibility to drug-induced oxidative collapse than the heterogeneous SKGT-4 line. Collectively, these findings demonstrate that bovine milk exosome encapsulation successfully bypasses the delivery barriers of EGCG, establishing a scalable and potent nanomedicine platform for refractory esophageal adenocarcinoma.