Properties of Native High‐Density Lipoproteins Inspire Synthesis of Actively Targeted In Vivo siRNA Delivery Vehicles |
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| Authors: | Kaylin M. McMahon Michael P. Plebanek Colby Shad Thaxton |
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| Affiliation: | 1. Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA;2. Walter S. and Lucienne Driskill Graduate Training Program in Life Sciences, Northwestern University, Chicago, IL, USA;3. Simpson Querrey Institute (SQI) for BioNanotechnology, Northwestern University, Chicago, IL, USA;4. Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA;5. International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA |
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| Abstract: | Efficient systemic administration of therapeutic short interfering RNA (siRNA) is challenging. High‐density lipoproteins (HDLs) are natural in vivo RNA delivery vehicles. Specifically, native HDLs: 1) load single‐stranded RNA; 2) are anionic, which requires charge reconciliation between the RNA and HDL, and 3) actively target scavenger receptor type B‐1 (SR‐B1) to deliver RNA. Emphasizing these particular parameters, templated lipoprotein particles (TLP), mimics of spherical HDLs, are employed and are self‐assembled with single‐stranded complements of, presumably, any highly unmodified siRNA duplex pair after formulation with a cationic lipid. Resulting siRNA templated lipoprotein particles (siRNA‐TLP) are anionic and tunable with regard to RNA assembly and function. Data demonstrate that the siRNA‐TLPs actively target SR‐B1 to potently reduce androgen receptor and enhancer of zeste homolog 2 proteins in multiple cancer cell lines. Systemic administration of siRNA‐TLPs demonstrated no off‐target toxicity and significantly reduced the growth of prostate cancer xenografts. Thus, native HDLs inspired the synthesis of a hybrid siRNA delivery vehicle that can modularly load single‐stranded RNA complements after charge reconciliation with a cationic lipid, and that function due to active targeting of SR‐B1. |
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| Keywords: | active delivery lipoproteins nanoparticles single‐stranded RNA short interfering iRNA |
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