Jiang Xinyi's team at Shandong University developed a drug delivery system based on Th17 cells that can be delivered across the blood-brain barrier to treat multiple sclerosis

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS), characterized by demyelinating, axonal damage, and neurodegeneration, for which there is currently no cure
.
The cause of MS is unknown, and it is thought that a complex interaction between multiple genetic and environmental factors contributes to the development
of MS.
More and more preclinical and clinical studies have shown that Th17 cells at the site of CNS lesions are involved in the occurrence and progression
of MS.

Th17 cells express high levels of IL-23 receptors and granzyme B to enable them to migrate through the blood-brain barrier (BBB) and subsequently contribute to chronic CNS inflammation
.
The massive infiltration of Th17 cells leads to an imbalance between Th17 cells and immunosuppressive Treg, which is closely related
to the occurrence and development of this autoimmune disease.
At the same time, Th17 cells are a kind of functionally adaptable, that is, plastic cells, and the in situ regulation of pro-inflammatory Th17 cells into anti-inflammatory Treg cells at the CNS inflammatory site may help the clearance of inflammation, which can be used as a therapeutic strategy
for MS.

(Aminooxy)-acetic acid (AOA) inhibits pyridoxal 5'-phosphate-dependent transaminases to reduce methylation of the FOXP3 locus and increase the expression of FOXP3, thereby inducing the transdifferentiation of Th17 cells into Treg cells
.
However, due to the presence of BBBs, the penetration efficiency of most drugs, including AOA, in the CNS is quite limited
.
Therefore, the development of drug delivery systems that can cross the BBB is essential
for CNS-site diseases such as MS.
Both clinical and preclinical evidence suggests that blood-borne Th17 cells can migrate through the BBB to MS lesions, resulting in massive infiltration of Th17 cells in the brain and aggravation
of local inflammation.
Therefore, Th17 cells are used as "Trojan horse" cell delivery vectors for therapeutic drugs to be delivered across the BBB cascade and homing to MS lesions
.

Recently, the team of Professor Xinyi Jiang of the School of Pharmacy of Shandong University published a report in the journal Advanced Materials entitled Trojan Horse Nanocapsule Enabled in Situ Modulation of the Phenotypic Conversion of Th17 Cells to Treg Cells for the Treatment of Multiple Research paper
by Sclerosis in Mice.

This study constructed a Th17 cell backpacking drug delivery system that can cross the blood-brain barrier and perform phenotypic conversion, and was successfully applied to the treatment
of multiple sclerosis animal models of chronic inflammatory demyelinating disease of the central nervous system.

Observing increased secretion of reactive oxygen species (ROS) in multiple sclerosis (MS) patients and in animal models, the research team first designed and constructed ROS-responsive nanocapsules (nC) for inflammatory phenotypic conversion drug (AOA) delivery to achieve precise drug release
at the site of inflammation.

Then, the drug carrier nanocapsule is attached to the surface of Th17 cells by conjugating maleimide groups on the surface of nC to free mercaptans on the cell surface to form the Th17 cell "Trojan" co-delivery system (Th17-nC).

In vitro culture found that nC conjugation does not alter the critical trans-BBB function of Th17 cells, but can convert Th17 cells to the Treg phenotype
by loading AOA.

After intravenous injection into MS model mice, Th17-nC migrates across the BBB and enriches
at the site of MS injury inflammation.
Locally produced ROS promotes AOA release and uptake by Th17 cells, which then induces the transdifferentiation of Th17 cells into anti-inflammatory Treg cells
in these lesion regions.
This phenotypic shift results in a domino-like immune response and may be broadly applicable to the treatment
of other autoimmune diseases.

Schematic diagram of Th17 cell backpack drug delivery system for CNS inflammatory site delivery and in situ phenotypic transdifferentiation of Th17 cells into anti-inflammatory Treg cells for MS treatment

In recent years, Professor Jiang Xinyi's team has made a series of important achievements in gene therapy and controlled delivery of nucleic acid drugs, which have been published in Nature Nanotechnology, Science Translational Medicine, Nature Communications, PNAS, Science Advances, Advanced Materials and other internationally renowned academic journals
。