title: Mechanistic insights into LDL nanoparticle-mediated siRNA delivery.
abstract: Although small interfering RNA (siRNA) can silence the expression of disease-related genes, delivery of these highly charged molecules is challenging. Delivery approaches for siRNAs are actively being pursued, and improved strategies are required for nontoxic and efficient delivery for gene knockdown. Low density lipoprotein (LDL) is a natural and endogenous nanoparticle that has a rich history as a delivery vehicle. Here, we examine purified LDL nanoparticles as carriers for siRNAs. When siRNA was covalently conjugated to cholesterol, over 25 chol-siRNA could be incorporated onto each LDL without changing nanoparticle morphology. The resulting LDL-chol-siRNA nanoparticles were selectively taken up into cells via LDL receptor mediated endocytosis, resulting in enhanced gene silencing compared to free chol-siRNA (38% gene knock down versus 0% knock down at 100 nM). However, silencing efficiency was limited by the receptor-mediated entrapment of the LDL-chol-siRNA nanoparticles in endolysosomes. Photochemical internalization demonstrated that endolysosome disruption strategies significantly enhance LDL-mediated gene silencing (78% at 100 nM).
authors.affiliation: Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Honglin
authors.initials: H
authors.lastname: Jin
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Lovell
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.forename: Qiaoya
authors.initials: Q
authors.lastname: Lin
authors.forename: Lili
authors.initials: L
authors.lastname: Ding
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Ng
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Pandey
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: Zheng
mesh_terms: D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D006801:Humans; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism*; D013499:Surface Properties
chemical_list: D008077:Lipoproteins, LDL; D034741:RNA, Small Interfering