Extracellular vesicles encapsulated with caspase-1 inhibitor ameliorate experimental autoimmune myasthenia gravis through targeting macrophages

Cysteinyl aspartate-specific proteinase-1 (caspase-1) is a multifunctional inflammatory mediator in many inflammation-related diseases. Previous studies show that caspase-1 inhibitors produce effective therapeutic outcomes in a rat model of myasthenia gravis. However, tissue toxicity and unwanted off-target effects are the major disadvantages limiting their clinical application as therapeutic agents. This study shows that dendritic cell-derived extracellular vesicles (EVs) loaded with a caspase-1 inhibitor (EVs-VX-765) are phagocytized mainly by macrophages, and caspase-1 is precisely expressed in macrophages. Furthermore, EVs-VX-765 demonstrates excellent therapeutic effects through a macrophage-dependent mechanism, and it notably inhibits the level of interleukin-1β and subsequently inhibits Th17 response and germinal center (GC) reactions. In addition, EVs-VX-765 demonstrates better therapeutic effects than routine doses of VX-765, although drug loading is much lower than routine doses, consequently reducing tissue toxicity. In conclusion, this study's findings suggest that EV-mediated delivery of caspase-1 inhibitors is effective for treating myasthenia gravis and is promising for clinical applications.