Functional shell engineering of bioactive wheat-seedling nanovesicles with chitosan derivatives for synergistic metabolic therapy via enhanced oral delivery.

Plant-derived exosome-like vesicles (PDEVs) have emerged as promising oral delivery carriers, yet their application is severely limited by gastrointestinal instability and poor intestinal absorption. To overcome these barriers, we developed a biohybrid nanoplatform by sequentially coating wheat-seedling PDEVs with trimethyl chitosan (TMC) and carboxymethyl chitosan (CMC) via layer-by-layer self-assembly. This engineering strategy confers enhanced physicochemical stability, effectively protecting the payload against gastric degradation while enabling targeted intestinal release. Mechanistically, the multifunctional shell promotes transepithelial transport by enhancing cellular internalization and reversibly modulating epithelial tight junctions. Importantly, this improved delivery enables synergistic immuno-metabolic effects between the loaded α-lipoic acid (ALA) and the carrier's endogenous bioactives (GABA and folic acid). In a metabolic syndrome cell model, the nanoplatform achieved therapeutic efficacy superior to free drug combinations by suppressing pro-inflammatory cytokines and regulating lipid metabolism. Furthermore, in a high-fat diet-induced zebrafish model, the system significantly reversed abdominal lipid accumulation and alleviated systemic oxidative stress. Overall, this work provides a generalizable surface-engineering strategy for stabilizing natural vesicle carriers and supports their application in synergistic oral metabolic therapy.