Linoleic acid co-administration promotes oral delivery of exenatide-loaded butyrate-decorated nanocapsules.

Epithelial cell entrance and trans-epithelial transport are two essential processes that directly affect the efficacy of oral delivery of nanocarriers. Herein, a hydroxyethyl starch-based nanocapsule dual decorated with butyrate and octadecylamine (ODA) was first constructed to enhance transporter-mediated endocytosis and trans-epithelial transport, while reducing exenatide (EXT) loss during absorption. The epithelial barrier was then treated with linoleic acid (LA), which functioned as a cell membrane fluidity regulator. This treatment further improved oral delivery efficiency by lowering the energy cost of endocytosis through fluidizing of the cell membrane and increasing monocarboxylate transporter 1 (MCT1) expression on cell surfaces. The findings revealed that LA upregulated MCT1 expression by 3.26-fold, increased the cellular uptake of nanocapsules co-modified with butyrate and ODA by 4.52-fold, decreased ATP consumption for uptake in LA-pretreated Caco-2 cells to only 18.64 % of that in untreated Caco-2 cells, and increased their transcellular transport by 1.72-fold in a Caco-2/HT29-MTX-E12 co-culture monolayer. Therefore, the oral administration of EXT-loaded Bu-PEG-ODA NCs with LA significantly enhanced the oral bioavailability of EXT (Bu-PEG-ODA NCs group: 10.10 %, Bu-PEG-ODA NCs + LA group: 14.84 %), leading to a significant hypoglycemic effect with a 16.06 % relative pharmacological availability. This dosing strategy exhibited efficacious blood glucose control and pancreatic function recovery capabilities in the type 2 diabetes rat model. This study presents a unique co-optimization strategy based on two key processes in the oral absorption of nanocarriers, yielding significant advancements in the oral bioavailability of nanomedicines and improving their therapeutic efficacy.