Engineered exosomes conferred with ROS-regulation and immuno-suppression for ameliorating lupus nephritis

Mesenchymal stromal cell-derived exosomes (MEXs) possess inherent homing capabilities, tissue repair abilities, and anti-inflammatory and immunomodulatory functions, making them a promising alternative for treating lupus nephritis (LN). In this study, we present an innovative engineered MEX that serves both as a reactive oxygen species (ROS) scavenger and a rapamycin carrier for targeted LN therapy. The nanohybrid (CEX@Rapa) was developed by chemically conjugating ceria (Ce) nanoparticles to rapamycin-loaded thiol-functionalized MEXs through a Michael addition reaction. The resulting nanohybrids demonstrate minimal toxicity, optimal drug loading efficiency, superior cellular uptake capability, and remarkable anti-oxidant, anti-damage, and anti-inflammatory properties. Upon systemic administration to MRL/lpr mice, these nanohybrids tend to accumulate and persist at the site of kidney inflammation, mitigating the excessive immune response and promoting kidney repair, leading to significant alleviation of LN symptoms through the independent and synergistic effects of MEXs, Ce nanoparticles, and rapamycin. Therefore, we believe that Ce-immobilized MEXs, as an enhanced drug nanocarrier with ROS-regulating and immunomodulatory capabilities, hold substantial promise for treating LN and other autoimmune diseases.