**3.5 Lymphatic barrier**

The process of crossing the blood-lymph barrier (BLyB) is regulated by various mechanisms including extravasation, overcoming of the interstitium, diffusion and passage through the mucosal barrier [106, 147]. In addition, the collagen reticular network (RN) hinders soluble substances from passing through [106, 148–153]. However, EVs possess certain characteristics that enable them to cross the BLyB. For instance, human ovarian cancer cell exosomes were found to be able to travel from the periphery to the lymph node in just a matter of minutes in rodents due to their small size [106, 154], and their lipidic rather than soluble nature seemed to enable them to cross the RN [106, 155].

Although EVs already possess intrinsic advantages that enable them to cross the BLyB, methods like microfluidic surface engineering have been conducted on EVs to modify them further as potential drug carriers for lymphoma treatment or other diseases related to the lymphatic system [106, 156, 157]. A recent study explored the modification of exosomes derived from bovine serum. α-D-mannose was added to the exosomes containing immune stimulators to enable them to interact with the mannose receptors on dendritic cells for uptake, and the exosomes were PEGylated. This has been found to enhance the internalisation of the exosomes by murine dendritic cells and to increase their localisation in the lymph nodes, paving the way for efficient delivery of immune stimulators *via* EVs *in vivo* as a potential form of drug therapy [158].
