Nanoparticle Targeting and Cholesterol Flux Through Scavenger Receptor Type B-1 Inhibits Cellular Exosome Uptake.
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.
Northwestern University, Feinberg School of Medicine, Department of Urology, Tarry 16-703, 303 E. Chicago Ave., Chicago, IL 60611 United States.|Simpson Querrey Institute for BioNanotechnology, 303 E. Superior St., Chicago, IL 60611 United States.
Michael P
MP
Plebanek
Feinberg Cardiovascular Research Institute, 303 E. Chicago Ave., Tarry 14-725, Chicago, IL 60611 United States.
R Kannan
RK
Mutharasan
Northwestern University, Feinberg School of Medicine, Department of Urology, Tarry 16-703, 303 E. Chicago Ave., Chicago, IL 60611 United States.
Olga
O
Volpert
University of Wyoming, Department of Molecular Biology, 1000 E. University Ave., Laramie, WY 82071 United States.|University of California at San Francisco, Department of Cell and Tissue Biology, San Francisco, CA 94143 United States.
Alexandre
A
Matov
University of Wyoming, Department of Molecular Biology, 1000 E. University Ave., Laramie, WY 82071 United States.
Jesse C
JC
Gatlin
Northwestern University, Feinberg School of Medicine, Department of Urology, Tarry 16-703, 303 E. Chicago Ave., Chicago, IL 60611 United States.|Simpson Querrey Institute for BioNanotechnology, 303 E. Superior St., Chicago, IL 60611 United States.|International Institute for Nanotechnology (IIN), Northwestern University, 2145 Sheridan Rd., Evanston, IL 60208 United States.
C Shad
CS
Thaxton
D000818:Animals; D001693:Biological Transport, Active; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism*; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D051122:Scavenger Receptors, Class B / Q000378:metabolism*
D008075:Lipoproteins, HDL; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D002784:Cholesterol