Nanoparticle-boosted myeloid-derived suppressor cell therapy for immune reprogramming in multiple sclerosis

Massive immune cell infiltration and persistent inflammation in the central nervous system (CNS) are key hallmarks of multiple sclerosis, an incurable autoimmune disease. Here, we report a myeloid-derived suppressor cell (MDSC)-based therapeutic strategy, named CNS Immune Targeting Enabled by MDSCs (CITED), which employs surface-decorated MDSCs carrying rapamycin nanoparticles (NPs) for targeted multimodal immune reprograming in the CNS. We show that NP decoration enhances MDSC immunomodulatory function, facilitates their trafficking to inflamed CNS regions, and increases NP accumulation within the CNS. In an experimental autoimmune encephalomyelitis (EAE) model, CITED exhibited robust therapeutic efficacy, resulting in reduced disease progression, improved motor function, and diminished myelin damage. Mechanistic studies reveal that CITED exerts its therapeutic effects by targeted reprogramming both innate and adaptive immune responses in CNS. Specifically, CITED inhibits immune cell infiltration, rebalances CD4 T cell phenotypes, and promotes the polarization of myeloid cells toward anti-inflammatory phenotypes. Collectively, CITED could provide a broadly effective approach for targeted immune restoration in multiple sclerosis and potentially other autoimmune diseases. Overall design: RNA seq profilling of myeloid derived suppressor cells (MDSC), MDSCs conjugated with blank NP(MDSC_NP_Blk) and MDSCs carrying rapamycin nanoparticles (MDSC_NP_CITED).