Engineered EVs for Oxidative Stress Protection

Abstract

Extracellular vesicles (EVs) are increasingly studied as vectors for drug delivery because they can transfer a variety of molecules across biological barriers. SerpinB3 is a serine protease inhibitor that has shown a protective anti-apoptotic function in a variety of stressful conditions. The aim of this study was to evaluate protection from oxidative stress-induced damage, using extracellular vesicles that overexpress SerpinB3 (EVs-SB3) in order to enhance the effect of extracellular vesicles on cellular homeostasis. EVs-SB3s were obtained from HepG2 cells engineered to overexpress SerpinB3 and they revealed significant proteomic changes, mostly characterized by a reduced expression of other proteins compared with EVs from non-engineered cells. These EV preparations showed a significantly higher protection from H2O2 induced oxidative stress in both the hepatoma cell line and in primary cardiomyocytes, compared to cells treated with naïve EVs or SerpinB3 alone, used at the same concentration. In conclusion, the induction of SerpinB3 transgene expression results in the secretion of EVs enriched with the protein product that exhibits enhanced cytoprotective activity, compared with naïve EVs or the nude SerpinB3 protein.

Novel Molecular Targets for Immune Surveillance of Hepatocellular Carcinoma

“…While SerpinB3 is undetectable in normal livers, its expression progressively increases during the evolution of chronic liver disease and HCC development [107,110]. Despite the protective effect of SerpinB3 in acute damage [111], its chronic expression in response to oxidative stress conditions plays a pivotal role in oncogenesis and in particular in HCC, affecting different cell activities that led to resistance to apoptotic cell death [112][113][114][115], increased cell proliferation and invasion [116].…”

“…protective effect of SerpinB3 in acute damage [111], its chronic expression in response to oxidative stress conditions plays a pivotal role in oncogenesis and in particular in HCC, affecting different cell activities that led to resistance to apoptotic cell death [112][113][114][115], increased cell proliferation and invasion [116].…”

SerpinB3: A Multifaceted Player in Health and Disease – Review and Future Perspectives

“…SerpinB3 has a protective role in acute damage [18], but its chronic overexpression acts as an oncogenic factor, leading to apoptosis resistance [19,20], cell proliferation, fibrosis and increased interleukin (IL)-6 signaling [24,25]. SerpinB3 expression increases in response to Tumor Necrosis Factor (TNF)- and Ras-driven inflammation [21,22] leading to NF-kB activation, IL-6 production and tumor growth [22,23].…”