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

Liver diseases pose a significant health burden worldwide, but hope is on the horizon thanks to advancements in nanomedicine. Mesenchymal stem cell-derived extracellular vesicles (EVs) have emerged as promising therapeutics due to their regenerative and immunomodulatory properties. However, concerns have been raised about their rapid clearance by the body’s immune system.

In a groundbreaking study, researchers at King’s College London have delved into the fascinating world of protein corona—the layer of proteins that coat EVs upon exposure to bodily fluids. By investigating how different culturing conditions and serum exposure affect the protein corona-EV complex, they’ve uncovered a game-changing strategy for liver disease therapy.

In vitro study simulating formation of primary protein corona (1st corona)
and secondary protein corona (2nd corona) on EVs and liposomes

Extended Data Fig. 1

(a) EV2D and (b) Negatively charged liposomes (LIP, as representative of synthetic particles with lipid bilayers) were incubated firstly with albumin labelled with Alexa fluor 488 (ALB-AF488) (1st corona) then with albumin labelled with Cyanide 5 (ALB-Cy5) (2nd corona). Fluorescence was evaluated by a plate reader to determine the degree of albumin adsorption. Results confirmed that EV precoating with ALB (1st corona) induces deposition of more albumin (2nd corona) on EVs (**p = 0.0015). This is mimicking EVs interaction with blood when injected intravenously. In case of LIP, quenching was observed. Data are presented as mean ± SD (n = 3, biologically independent samples) with two-tailed unpaired t-Test analysis. 

Their findings reveal that specific proteins, such as albumin, create a unique signature on the surface of EVs. This signature acts as a camouflage, redirecting EVs away from phagocytic cells towards liver cells, including hepatocytes, liver sinusoidal endothelial cells, and hepatic stellate cells. This phenomenon significantly enhances the uptake of EVs by liver cells, improving their therapeutic efficacy.

But the innovation doesn’t stop there. By precoating EVs with albumin, researchers have developed a targeted delivery system that evades immune detection and enhances liver cell uptake—a breakthrough in liver disease therapy.

This work addresses a critical challenge in the field of nanomedicine: how to tailor EVs for efficient delivery to target tissues while avoiding immune clearance. By harnessing the power of protein corona, researchers are paving the way for more effective and targeted therapies for liver diseases.

As we continue to unravel the mysteries of EVs and their interactions with the body, the future of liver disease therapy looks brighter than ever. With innovative strategies like protein corona engineering, we’re one step closer to transforming the landscape of liver disease treatment and improving the lives of millions worldwide.

Liam-Or R, Faruqu FN, Walters A, Han S, Xu L, Wang JT, Oberlaender J, Sanchez-Fueyo A, Lombardi G, Dazzi F, Mailaender V, Al-Jamal KT. (2024) Cellular uptake and in vivo distribution of mesenchymal-stem-cell-derived extracellular vesicles are protein corona dependent. Nat Nanotechnol [Epub ahead of print]. [article]

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