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Abstract
Exosomes are nanoscale vesicles that mediate intercellular communication. Cellular exosome uptake mechanisms are not well defined partly due to the lack of specific inhibitors of this complex cellular process. Exosome uptake depends on cholesterol-rich membrane microdomains called lipid rafts, and can be blocked by non-specific depletion of plasma membrane cholesterol. Scavenger receptor type B-1 (SR-B1), found in lipid rafts, is a receptor for cholesterol-rich high-density lipoproteins (HDL). We hypothesized that a synthetic nanoparticle mimic of HDL (HDL NP) that binds SR-B1 and removes cholesterol through this receptor would inhibit cellular exosome uptake. In cell models, our data show that HDL NPs bind SR-B1, activate cholesterol efflux, and attenuate the influx of esterified cholesterol. As a result, HDL NP treatment results in decreased dynamics and clustering of SR-B1 contained in lipid rafts and potently inhibits cellular exosome uptake. Thus, SR-B1 and targeted HDL NPs provide a fundamental advance in studying cholesterol-dependent cellular uptake mechanisms.
Highlights
Exosomes transport molecular cargo to and from cells as a means of intercellular communication[1,2], and play a fundamental role in biology[3]
Our data demonstrate that high-density lipoproteins (HDL) NPs are a targeted and functional nanoconjugate that potently inhibit cellular exosome uptake in cultured melanoma, endothelial, and macrophage cells
A model (Fig. 8a,b) is proposed for HDL-like nanoparticle (HDL NP) whereby tight binding to Scavenger receptor type B-1 (SR-B1) in lipid rafts modulates free and esterified cholesterol flux through this receptor
Summary
Exosomes transport molecular cargo to and from cells as a means of intercellular communication[1,2], and play a fundamental role in biology[3]. Of these interactions may open avenues for studying intercellular communication and lead to new therapies[19] Key to this effort is the identification of targeted agents that potently inhibit cellular exosome uptake[19]. Recent data show that exosome uptake by target cells is dependent upon the integrity of plasma membrane microdomains known as lipid rafts, which are known to be rich in cholesterol[20]. Scavenger receptor type B-1 resides in plasma membrane lipid rafts[24] where it maintains cholesterol balance and enables the uptake of extracellular material and cell signaling[25]. Due to the localization of SR-B1 to lipid rafts and the dependence of exosome uptake on cholesterol balance in the plasma membrane, we hypothesized that specific targeting of SR-B1 with cholesterol binding HDL NPs26–29 would disrupt cellular exosome uptake. We explored exosomes derived from cultured melanoma cells due to the established importance of the uptake of these exosomes by melanoma and other target cells[11,15,30,31], and because melanoma exosomes have been shown to promote disease progression whereby targeted inhibitors of this process may be translationally relevant[30,32]
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