Cellular uptake and in vivo distribution of mesenchymal-stem-cell-derived extracellular vesicles are protein corona dependent

Abstract

Extracellular vesicles (EVs) derived from mesenchymal stem cells are promising nanotherapeutics in liver diseases due to their regenerative and immunomodulatory properties. Nevertheless, a concern has been raised regarding the rapid clearance of exogenous EVs by phagocytic cells. Here we explore the impact of protein corona on EVs derived from two culturing conditions in which specific proteins acquired from media were simultaneously adsorbed on the EV surface. Additionally, by incubating EVs with serum, simulating protein corona formation upon systemic delivery, further resolved protein corona–EV complex patterns were investigated. Our findings reveal the potential influences of corona composition on EVs under in vitro conditions and their in vivo kinetics. Our data suggest that bound albumin creates an EV signature that can retarget EVs from hepatic macrophages. This results in markedly improved cellular uptake by hepatocytes, liver sinusoidal endothelial cells and hepatic stellate cells. This phenomenon can be applied as a camouflage strategy by precoating EVs with albumin to fabricate the albumin-enriched protein corona–EV complex, enhancing non-phagocytic uptake in the liver. This work addresses a critical challenge facing intravenously administered EVs for liver therapy by tailoring the protein corona–EV complex for liver cell targeting and immune evasion.

Dual-mode action of scalable, high-quality engineered stem cell-derived SIRPα-extracellular vesicles for treating acute liver failure

“…28 To address this issue, recent studies have enhanced EV targeting by forming a protein corona on their surface, specifically coating C-EVs with albumin to improve delivery to hepatocytes beyond macrophages. 28 Additionally, surface engineering of EVs has been used to enhance targeted delivery to specific cells, thereby enhancing therapeutic efficacy. [29][30][31][32] Our findings prove that SIRP expression on EVs not only mitigates necroptosis but also promotes effective accumulation in CD47-overexpressing liver tissues and hepatocytes extending beyond macrophages in acute inflammatory conditions.…”

Molecular Determinants Involved in the Docking and Uptake of Tumor-Derived Extracellular Vesicles: Implications in Cancer

“…Both the intracellularly and extracellularly formed types of protein coronas may be relevant for EVs function [ 51 ]. Interestingly, Liam-Or et al have very recently reported that the composition of the protein corona that wraps EVs dictates crucial properties of these vesicles, including their in vivo distribution as well as their targeting and uptake by specific recipient cells [ 52 ].…”

Looking back, moving forward: protein corona of lipid nanoparticles

“…Following administration, the PC will become a responsive structure that can bind to the target site, thereby eliciting the therapeutic effect. 184 Tissues lacking target sites will remain unresponsive to the structure, mitigating potential adverse reactions. Tincu et al applied BSA coronas to NLCs loaded with piperine (Pip) to alter the delivery capacity of NLCs to colon, ovary, and breast cancer cells.…”