Enucleated cells with Nectin-1 overexpression capture HSV-1 and promote viral elimination for herpes simplex encephalitis therapy.

Herpes simplex encephalitis (HSE) is a life-threatening disease of the central nervous system caused by herpes simplex virus type 1 (HSV-1). Despite being a standard treatment, antiviral acyclovir and its derivatives often face limitations in clinical application due to their side effects and viral drug resistance. Inspired by viral entry through recognition of nectin-1 on the host cell surface, we engineered enucleated mesenchymal stem cells with high nectin-1 expression (eMSCs) to serve as "decoys" for capturing HSV-1. We found that eMSCs competitively captured the virus in the presence of neurons while inhibiting its replication and spread by removing the nucleus in advance. Interestingly, due to the absence of nuclei, eMSCs capturing the virus trigger macrophage efferocytosis through intrinsic apoptosis after approximately 60 h, thereby accelerating existing viral clearance. This is a property lacking in current antiviral drugs, including ACV. In summary, this strategy significantly improved the quality of life of HSE mice.