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

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.

N-Sulfonyl amidine polypeptides: new polymeric biomaterials with conformation transition responsive to tumor acidity

“…20–22 Even though numerous pH-triggered drug-delivery systems have been developed, most have focused on the responsiveness to intracellular pH. 23–30 Less attention has been paid to the development of nanocarriers that can respond sensitively to the acidic extracellular environment of the tumor because of the slight pH change (from 7.4 to 6.8), relatively weak acidity, and structure limitation. 31–34 Currently, only maleic acid amides, 34,35 hydrazones, 36,37 imines, 38,39 and sulfonamides 40–44 have been reported with regard to responsiveness to the weak acidic environment.…”

Inhaled immunoantimicrobials for the treatment of chronic obstructive pulmonary disease

“…However, effective nebulization therapy is greatly challenged by the multiple pathophysiological barriers (26)(27)(28)(29)(30). On the one hand, COPD is characterized by hypersecretion of mucus in the upper airway and bronchi, which is enriched in negatively charged mucin glycoproteins (31)(32)(33). Thus, after nebulization, positively charged antimicrobials tend to become trapped by the viscous mucus layer lining above the bronchial epithelium owing to strong electrostatic attraction with mucin (34), and they are subsequently cleared due to rapid mucus turnover (35)(36)(37).…”

Chitosan-Based Nano-Smart Drug Delivery System in Breast Cancer Therapy

“…Polymeric NPs (PNPs) are submicron colloidal particles broadly used in drug delivery systems, owing to the relatively easy attachment of targeting ligands to the surface of NPs. Surface modification of these PNPs with targeting ligands enables recognition by specific receptors or ligand-binding sites that are overexpressed on cancer cells or at target sites, for the controlled release of loaded drugs [ 25 , 26 , 27 , 28 ]. The rational design of targeted drug delivery systems based on PNPs involves taking into consideration their composition, solubility, crystallinity, molecular weight, backbone stability, hydrophobicity and polydispersity.…”