Strategies to functionalize extracellular vesicles against HER2 for anticancer activity

Cell-secreted extracellular vesicles (EVs) are membranous particles highly heterogeneous in size and molecular cargo. Comprehensively, released EV sub-populations can show a wide range and selection of different protein, RNA, and lipid species, complementing cell communication signals. Recently, EVs represent a new source for developing targeted delivery systems. EVs are stable in biofluids, intrinsically biocompatible with low immunogenicity, and capable of transferring cargo molecules into “recipient” cells. The immune-mediated recognition represents a popular approach to functionalize and direct EVs towards receptor-positive cell populations. The human epidermal growth factor receptor 2 (HER2, also known as neu or ERBB2) is a tyrosine kinase of clinical relevance, targeted by several available antibodies, and a model receptor used to test the biodistribution and anticancer activity of bioformulations, including EVs. Here, we focus on recent strategies adopted for EV functionalization with fusion ligands able to recognize HER2, covering the enhanced expression of membrane-fusion proteins in “EV-donor” cells as well as post-isolation EV-surface modifications.