HBEGF/EGFR pathway activation by hUC-MSCs improves cognitive outcomes in anti-NMDAR encephalitis

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune disorder that impairs cognitive function. In this study, we investigated the impact of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on cognitive recovery in anti-NMDAR encephalitis. Our findings demonstrate that heparin-binding epidermal growth factor-like growth factor (HBEGF), a key functional factor secreted by hUC-MSCs, plays a pivotal role in ameliorating cognitive dysfunction. We elucidated that the HBEGF/epidermal growth factor receptor (EGFR) signaling pathway contributes to the enhancement of cognitive function following hUC-MSC exposure. Importantly, we employed a novel exosome-based intracellular therapeutic protein delivery technology-the mMaple3-mediated protein loading and release from exosomes (MAPLEX) system-for targeted HBEGF delivery. This approach facilitated a controlled, light-induced release of HBEGF from the exosomal membrane. Collectively, these findings support the involvement of HBEGF in mediating cognitive improvement in anti-NMDAR encephalitis induced by hUC-MSCs. Additionally, the MAPLEX system emerges as an effective delivery platform for HBEGF, potentially opening new avenues for the treatment of anti-NMDAR encephalitis.