Trojan Horse Nanocapsule Enabled In Situ Modulation of the Phenotypic Conversion of Th17 Cells to Treg Cells for the Treatment of Multiple Sclerosis in Mice

Th17/Treg imbalance is closely related to the occurrence and development of multiple sclerosis (MS), and the transdifferentiation of Th17 cells into Treg cells may contribute to the resolution of inflammation, presenting a therapeutic strategy for MS. To modulate this phenotypic shift in situ, a “Trojan horse”‐like hybrid system, nanocapsule‐coupled Th17 cells, is reported for MS treatment. Following intravenous injection into MS mice, the hybrid system efficiently transmigrates across the blood–brain barrier and homes to the inflamed MS niche. (Aminooxy)‐acetic acid, a transdifferentiation inducer, is locally released upon the production of ROS and in turn taken up by Th17 cells. It is demonstrated that the Trojan horse hybrid system enables in situ phenotypic transdifferentiation of Th17 cells into anti‐inflammatory Treg cells. This phenotypic conversion leads to a domino‐like immune response that is conducive to MS therapy. Overall, this work highlights a new pathway for accurate modulation of the phenotypes of adoptively transferred cells in situ, from proinflammatory to anti‐inflammatory for MS therapy, and may be broadly applicable for patients suffering from other autoimmune diseases. Nanocapsule (nC)‐coupled Th17 cells transmigrates across the blood–brain barrier and homes to the inflamed MS niche in a “Trojan Horse”‐like manner. Upon ROS stimulation, (Aminooxy)‐acetic acid is released from the nC, and subsequently enables in situ transformation of Th17 into Treg cells. This phenotypic conversion leads to a domino‐like immune response that is conducive to MS therapy.