Redirecting the route: Monocyte-mediated delivery of oHSV-1 across a human BBB-on-chip model

Oncolytic viruses (OVs) that selectively replicate within cancer cells represent a promising therapeutic strategy for refractory or difficult-to-treat tumors such as Glioblastoma (GBM). In this study, we develop and validate a human microfluidic blood brain barrier (BBB) model to evaluate the potential of cell-based OVs delivery targeting the central nervous system. We demonstrate that circulating leukocytes (monocytes), serve as effective carrier cells for the delivery of a neuroattenuated strain of oncolytic herpes simplex virus type 1 (oHSV-1) to GBM. Human monocytes infected with oHSV-1 and perfused through the device successfully traverse the BBB and migrate toward human GBM spheroids, where they deliver the virus and initiate infection. Notably, monocyte-mediated oHSV-1 delivery to the tumor occurs with <b>minimal involvement of BBB infection</b> and remains effective even in the presence of anti-HSV-1 antibodies, commonly found in the general population. In contrast, free oHSV-1 infects BBB-resident cells and is neutralized by circulating human immunoglobulins. These findings highlight the potential of monocyte-based oHSV-1 delivery as a targeted, immune-shielded strategy for GBM therapy.