Stimuli-responsive self-assembled dendrimers for oral protein delivery

[Display omitted] Oral delivery of protein is very challenging for therapeutic applications due to protein instability and degradability. Herein we synthesized benzoboroxole-containing multi-armed poly(ethylene glycol) amphiphilic dendrimers sensitive to both pH and glucose. The multi-branched structure of dendrimer facilitated its self-assembly into micelles in aqueous solution and exhibited good encapsulation of insulin just by simply mixing with insulin solution. The insulin loaded micelles were stable under strong acidic condition and showed glucose-responsive insulin release at physiological pH. The reversible binding between benzoboroxole and glucose can effectively regulate the disassembly of micelles and insulin release rate, which in turn stabilizes blood sugar fluctuations. Utilizing a mouse model of type 1 diabetes, it was demonstrated that these insulin loaded micelles could successfully control the blood glucose levels under a normoglycemic state and avoid the risk of hypoglycemia. Therefore, this smart delivery system shows great potential to significantly improve the effect of oral protein therapy.