Strategies to functionalize extracellular vesicles against HER2 for anticancer activity

Abstract

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.

Encapsulation and assessment of therapeutic cargo in engineered exosomes: a systematic review

“…Surface display of antibody fragments that bind unique cellular epitopes is another common targeting approach. For example, Lamp2b can fuse with an anti-HER2 nanobody and direct exosomes to HER2-overexpressing breast cancer cells, while exosomes displaying anti-EGFR nanobody are found to suppress EGFR signaling and reduce proliferation in triple negative breast cancer cells [ 43 ]. Single chain variable fragments (scFv) against tumor antigens have also been anchored using hydrophobic membrane intercalating peptides or enzymatic lipidation, and the scFv-decorated exosomes are found to bind and get internalized by target cancer cells [ 44 ].…”

CD81-guided heterologous EVs present heterogeneous interactions with breast cancer cells

“…Taking advantage of HER2 as a model receptor, several EV functionalization strategies have been proposed, starting from the manipulation of EV-donor cells ( pre-isolation strategies) or directly modifying EVs ( post-isolation strategies). Different proteins have been exploited to anchor HER2-targeting moieties to EV surface, including transmembrane proteins or membrane-associated domains, also with Trastuzumab portions (Gurrieri and D’Agostino, 2022). However, the contribution of exposed receptors to the cell-targeting spectrum of vesicles remains elusive, especially of heterologous EVs interacting with different recipient cells.…”