Bioinspired butyrate-functionalized nanovehicles for targeted oral delivery of biomacromolecular drugs

Abstract Ligand-functionalization can increase the affinity of nanoparticles (NPs) with targeted cells. However, one major defect of ligands still exists in oral administration: limited receptor recognition. The hindrance of mucus network and deactivation of enzymes severely challenge the targeting efficiency of macromolecular ligands. Inspired by “molecular exchange” between intestinal microbiota and host cells, we anchored microbiota metabolite butyrate on classical “mucus-inert” polyethylene glycol (PEG) NPs. Butyrate has unique advantages of low molecule weight, high hydrophilicity and chemical stability. Interestingly, in vitro mucus-permeability and in vivo mucus distribution of PEG NPs were not impaired by butyrate-functionalization. Enhanced cellular uptake was achieved via specific interaction between butyrate and the monocarboxylate transporter (MCT) on cell membranes, which subsequently ameliorated transepithelial transport and intestinal absorption in the ileum. In vitro safety assessment validated the non-toxicity of butyrate-modification. Finally, insulin-loaded Bu-PEG NPs generated a stronger hypoglycemic response on diabetic rats and 2.87-fold higher oral bioavailability compared with bare PEG NPs. This study demonstrated that butyrate-functionalization could improve the intestinal absorption of macromolecules by overcoming multiple obstacles in the gastrointestinal tract, providing a promising active targeting strategy for oral administration.