Nat Commun Shanghai Institute of Materia Medica: Jointly constructs a surface function biomimetic nanodrug carrier to improve the effect of oral insulin therapy

Diabetes is a chronic metabolic disease
that seriously 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 not only causes pain and inconvenience to patients, but also leads to peripheral hyperinsulinemia, resulting in side effects
such as hypoglycemia and obesity.
In contrast, oral insulin is more acceptable
to patients because of its painless and convenient administration.
However, on the one hand, the physiological barrier in the human gastrointestinal tract greatly limits the oral absorption efficiency of insulin; On the other hand, after insulin is absorbed orally into the bloodstream, it also 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 concentration of insulin in the liver is about 2-3 times that of
peripheral tissues.
Therefore, 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.
In summary, oral delivery of insulin faces significant challenges
.

In response to the above challenges and inspired by the unique surface and functional characteristics of the virus, the Gan Yong team of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences and the Wei Gang team of Fudan University published the relevant research results
online in Nature Communications on November 4, 2022.
In this achievement, a biomimetic viral multifunctional nanocarrier (Pep/Gal-PNP)
with surface ligand switchability was designed.
After oral administration, first 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 transmembrane peptide fragment at one end, mediating the nanocarrier to efficiently cross the intestinal mucosal barrier.
After entering the bloodstream, 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 to function (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, it restored the high hepato-peripheral high insulin concentration gradient in diabetic rats, significantly increased the storage of liver glycogen after long-term administration, which was about 7.
2 times that of the control group, and effectively improved sugar utilization
.
This study proposes a new oral insulin delivery strategy, which can efficiently overcome the intestinal mucosal barrier and accurately target the liver by simulating the conformational changes of viral surface proteins, 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 ultimately improve the oral therapeutic effect
of insulin.

Yang Tiantian, a doctoral student at the Shanghai Institute of Materia Medica, is the first author of the paper, and researcher Gan Yong of the Shanghai Institute of Materia Medica, and Professor Wei Gang of Fudan University are the corresponding authors
of the paper.
This research work was supported
by the National Natural Science Foundation of China and the Fudan University-Shanghai Institute of Materia Medica.

Full text link: