Ligand-switchable nanoparticles resembling viral surface for sequential drug delivery and improved oral insulin therapy

Tiantian Yang, Aohua Wang, Di Nie, Weiwei Fan, Xiaohe Jiang, Miaorong Yu, Shiyan Guo, Chunliu Zhu, Gang Wei () and Yong Gan ()
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Tiantian Yang: Chinese Academy of Sciences
Aohua Wang: Chinese Academy of Sciences
Di Nie: Chinese Academy of Sciences
Weiwei Fan: Chinese Academy of Sciences
Xiaohe Jiang: Chinese Academy of Sciences
Miaorong Yu: Chinese Academy of Sciences
Shiyan Guo: Chinese Academy of Sciences
Chunliu Zhu: Chinese Academy of Sciences
Gang Wei: Fudan University
Yong Gan: Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Mutual interference between surface ligands on multifunctional nanoparticles remains a significant obstacle to achieving optimal drug-delivery efficacy. Here, we develop ligand-switchable nanoparticles which resemble viral unique surfaces, enabling them to fully display diverse functions. The nanoparticles are modified with a pH-responsive stretchable cell-penetrating peptide (Pep) and a liver-targeting moiety (Gal) (Pep/Gal-PNPs). Once orally administered, the acidic environments trigger the extension of Pep from surface in a virus-like manner, enabling Pep/Gal-PNPs to traverse intestinal barriers efficiently. 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 to the maintenance of glucose homeostasis for effective diabetes management. Overall, this study provides a promising approach to achieving full potential of diverse ligands on multifunctional nanoparticles.

Date: 2022
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DOI: 10.1038/s41467-022-34357-8

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