The placenta is a fetal-derived organ that facilitates the exchange of nutrients, gases, and waste products between the mother and fetus during pregnancy. Additionally, the placenta serves as both a physical and immunological barrier, protecting the fetus against pathogens [1]. However, some viruses, including rubella, cytomegalovirus (CMV), herpes simplex virus (HSV), Zika virus (ZIKV), HIV, lymphocytic choriomeningitis virus (LCMV), hepatitis B virus (HBV), and other pathogens such as Toxoplasma gondii and Treponema pallidum can breach placental defenses, enter fetal circulation, and cause pregnancy complications and adverse fetal outcomes [1]. To traverse the placenta, viruses employ a variety of routes, including receptor-mediated entry, immune cell ‘Trojan horse’ entry, paracellular entry through disrupted tight junctions, transcytosis, and other routes 2, 3. This review highlights two emerging viral routes, namely, tunneling nanotubes (TNTs) and extracellular vesicles (EVs), which viruses exploit to access, persist in, and/or disrupt placental homeostasis.

The human placenta, derived from trophectoderm, is composed of anchoring and floating villi [4]. These villi are lined by two layers of trophoblasts: an inner layer of mononucleated cytotrophoblasts (CTBs) and an outer layer of multinucleated CTBs that differentiate into syncytiotrophoblasts (STBs). At the tip of anchoring villi, CTBs also differentiate into extravillous trophoblasts (EVTs), which invade the maternal endometrium and remodel spiral arteries. Placental cells in the anchoring villi are in direct contact with the maternal endometrium, while those in the floating villi interact with maternal immune cells circulating in the intervillous space (Figure 1).

Communication between placental cells and the maternal endometrial and immune cells is essential for establishing and maintaining a healthy pregnancy [5]. TNTs and EVs have recently emerged as key intercellular communication pathways, enabling the exchange of biomolecules through secreted signals or direct cell-to-cell contact [6]. Descriptions of TNTs in the placenta are emerging in the literature 7, 8, 9••, while EVs are increasingly recognized for their role in modulating immune response at the maternal–fetal interface [5]. During viral infection, both TNTs and EVs can be hijacked to facilitate viral dissemination, evade immune surveillance, and modulate host responses 10, 11. This review will focus on the roles of virally hijacked TNTs or EVs during infection and immunomodulation at the maternal–fetal interface. We will highlight viruses known to cross the maternal–fetal interface, such as ZIKV, HIV, CMV, HSV, LCMV, and HBV, and those that infect the placenta but are rarely vertically transmitted, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory syncytial virus (RSV) (Table 1).