Virus surface-inspired ligand-switchable nanoparticles enable sequential drug delivery for improved oral insulin therapy

Abstract Mutual interference between surface ligands on multifunctional nanoparticles remains a significant obstacle to achieving the optimal drug-delivery efficacy. Inspired by viruses that modulate surface proteins conformation to enable sequential display of diverse functions, we develop ligand-switchable nanoparticles modified with a pH-responsive stretchable cell-penetrating peptide (Pep) and a liver-targeting moiety (Gal) (Pep/Gal-PNPs). The acidic environments encountered after oral administration trigger the extension of Pep from the surface in a virus-like manner, enabling Pep/Gal-PNPs to efficiently traverse intestinal barriers. Subsequently, Gal is exposed by Pep folding at physiological pH, thereby allowing the specific targeting of Pep/Gal-PNPs to the liver. As a proof-of-concept, insulin-loaded Pep/Gal-PNPs are fabricated which exhibit effective intestinal absorption and excellent hepatic deposition of insulin. Crucially, Pep/Gal-PNPs increase hepatic glycogen production by 7.2-fold, contributing the maintenance of glucose homeostasis for effective diabetes management. Overall, this study provides a promising approach to achieve full potential of diverse ligands on multifunctional nanoparticles.