Intercellular highways of viral spread: tunneling nanotubes and extracellular vesicles at the maternal–fetal interface

Abstract

The placenta serves as both a conduit and a barrier, facilitating nutrient exchange while shielding the fetus from pathogens. Despite these defenses, several viruses, including ZIKV, CMV, HSV, HIV, LCMV, and HBV, can breach the placental barrier, while others like SARS-CoV-2 and RSV infect placental cells without consistent vertical transmission. Emerging evidence highlights two underexplored intercellular communication mechanisms, tunneling nanotubes (TNTs) and extracellular vesicles (EVs), as critical pathways exploited by viruses to disseminate, modulate immunity, and disrupt placental homeostasis. This review discusses how virally hijacked TNTs and EVs facilitate transmission and immune evasion at the maternal–fetal interface, emphasizing the need to further understand these mechanisms in the context of pregnancy and fetal health.