// Kaylin M. McMahon 1, * , Cristina Scielzo 2, 3, * , Nicholas L. Angeloni 1 , Elad Deiss-Yehiely 1 , Lydia Scarfo 2, 3 , Pamela Ranghetti 2, 3 , Shuo Ma 4 , Jason Kaplan 4, 5 , Federica Barbaglio 3 , Leo I. Gordon 4 , Francis J. Giles 4, 5 , C. Shad Thaxton 1, 4, 6, 7 , Paolo Ghia 2, 3 1 Department of Urology, Feinberg School of Medicine, Northwestern University, Tarry, Chicago, IL, USA 2 Universita Vita-Salute San Raffaele, Milan, Italy 3 Strategic Research Program On CLL and Unit of B cell Neoplasia, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy 4 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA 5 Developmental Therapeutics Program of The Division of Hematology Oncology, Feinberg School of Medicine, Chicago, IL, USA 6 Simpson Querrey Institute (SQI) for BioNanotechnology, Chicago, IL, USA 7 International Institute for Nanotechnology, Evanston, IL, USA * These authors equally contributed to this work Correspondence to: C. Shad Thaxton, email: cthaxton003@md.northwestern.edu Paolo Ghia, email: ghia.paolo@hsr.it Keywords: lipoprotein, leukemia, scavenger receptor type B-I, nanoparticle, biomaterials Received: June 29, 2016 Accepted: December 26, 2016 Published: January 04, 2017 ABSTRACT Chronic lymphocytic leukemia (CLL) remains incurable despite the introduction of new drugs. Therapies targeting receptors and pathways active specifically in malignant B cells might provide better treatment options. For instance, in B cell lymphoma, our group has previously shown that scavenger receptor type B-1 (SR-B1), the high-affinity receptor for cholesterol-rich high-density lipoproteins (HDL), is a therapeutic target. As evidence suggests that targeting cholesterol metabolism in CLL cells may have therapeutic benefit, we examined SR-B1 expression in primary CLL cells from patients. Unlike normal B cells that do not express SR-B1, CLL cells express the receptor. As a result, we evaluated cholesterol-poor synthetic HDL nanoparticles (HDL NP), known for targeting SR-B1, as a therapy for CLL. HDL NPs potently and selectively induce apoptotic cell death in primary CLL cells. HDL NPs had no effect on normal peripheral blood mononuclear cells from healthy individuals or patients with CLL. These data implicate SR-B1 as a target in CLL and HDL NPs as targeted monotherapy for CLL.