Shanghai Institute of Pharmaceutical Products et al. constructed surface functional biomimetic nanodrug carriers

Diabetes is a chronic metabolic disease
that threatens human health.
At present, the main clinical treatment for patients with type I diabetes and type II diabetes mellitus is frequent subcutaneous insulin injection, which causes pain and inconvenience to patients and leads to peripheral hyperinsulinemia, resulting in side effects
such as hypoglycemia and obesity.
In contrast, oral insulin is more acceptable
to patients due to its painless and convenient administration.
However, on the one hand, physiological barriers in the human gastrointestinal tract limit the efficiency of oral absorption of insulin; On the other hand, after oral absorption of insulin into the bloodstream, it faces the dilemma
of effective accumulation at the target site.
Under normal physiological conditions, insulin is secreted by pancreatic islet β cells and mainly acts on the liver, and the insulin concentration in the liver is about 2-3 times that of
peripheral tissues.
Oral insulin needs to efficiently overcome the intestinal mucosal absorption barrier and target enrichment to function in the liver, so as to simulate the secretion pattern of endogenous insulin and improve the utilization and distribution
of glucose in the body.
As a result, oral delivery of insulin presents challenges
.

On November 4, inspired by the unique surface and functional characteristics of the virus, Gan Yong's team from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and Wei Gang's team from Fudan University, published relevant research results
online in Nature Communications.
In this study, a surface ligand-convertible viral biomimetic multifunctional nanocarrier (Pep/Gal-PNP)
was designed.
After oral administration, in the acidic gastrointestinal environment, the Pep ligand on the surface of Pep/Gal-PNP can mimic the spike protein on the surface of the enveloped virus, and the structure stretches and exposes the membrane peptide fragment at one end, mediating the nanocarrier to efficiently cross the intestinal mucosal barrier.
After entering the blood, under physiological pH conditions, the Pep ligand structure folds, and the Gal ligand on the surface of Pep/Gal-PNP is exposed and binds to the desialic acid glycoprotein receptor (ASGPR) on the surface of hepatocytes, thereby specifically delivering insulin to the liver (Figure 1).

The results of in vivo studies showed that Pep/Gal-PNP was significantly absorbed on the villi of the small intestine after oral administration, and was mainly distributed in the liver (about 71.
9% of the total absorption).

In rat models of type I diabetes, Pep/Gal-PNP showed good hypoglycemic effects
.
More importantly, Pep/Gal-PNP restored the high hepato-peripheral high insulin concentration gradient in diabetic rats, and at the same time, the storage of liver glycogen was significantly increased after long-term administration, which was about 7.
2 times that of the control group, effectively improving sugar utilization
.
This study proposes a new oral insulin delivery strategy, that is, by simulating the conformational changes of viral surface proteins, it can efficiently overcome the intestinal mucosal barrier and accurately target the liver, so as to achieve the rational disposal of blood glucose in the body under the pathological condition of diabetes, help maintain blood glucose homeostasis, and improve the oral therapeutic effect
of insulin.

The research work was supported
by the National Natural Science Foundation of China and the Fudan University-Shanghai Institute of Materia Medica.

Construction of biomimetic viral nanocarriers with surface ligand conversion and in vivo delivery