Abstract
Lipid nanoparticles (LNPs) constitute a facile and scalable approach for delivery of payloads to human cells. LNPs are relatively immunologically inert and can be produced in a cost effective and scalable manner. However, targeting and delivery of LNPs across the blood–brain barrier (BBB) has proven challenging. In an effort to target LNPs composed of an ionizable cationic lipid (DLin-MC3-DMA), cholesterol, the phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG 2000) to particular cell types, as well as to generate LNPs that can cross the BBB, we developed and assessed two approaches. The first was centered on the BBB-penetrating trans-activator of transcription (Tat) peptide or the peptide T7, and the other on RNA aptamers targeted to glycoprotein gp160 from human immunodeficiency virus (HIV) or C-C chemokine receptor type 5 (CCR5), a HIV-1 coreceptor. We report herein a CCR5-selective RNA aptamer that acts to facilitate entry through a simplified BBB model and that drives the uptake of LNPs into CCR5-expressing cells, while the gp160 aptamer did not. We further observed that the addition of cell-penetrating peptides, Tat and T7, did not increase BBB penetration above the aptamer-loaded LNPs alone. Moreover, we found that these targeted LNPs exhibit low immunogenic and low toxic profiles and that targeted LNPs can traverse the BBB to potentially deliver drugs into the target tissue. This approach highlights the usefulness of aptamer-loaded LNPs to increase target cell specificity and potentially deliverability of central-nervous-system-active RNAi therapeutics across the BBB.
Highlights
Lipid nanoparticles (LNPs) represent an effective platform for delivering small molecules, RNA, or DNA into target cells [1]
While noncomplexed LNPs had an average size of 62.4 nm and a zeta potential (ZP) of −2.9 mV, LNPs mixed with GP160:A-1 and chemokine receptor type 5 (CCR5):G-3 displayed average sizes of 57.3 nm and 91.9 nm, respectively, as well as a more negative ZP (−11 mV and −9.4 mV, respectively, Table 2)
We further show that LNPs generally exhibit a low immunogenic and toxic profile and that RNA aptamers can act as potential enhancers to effectuate the delivery of LNPs into the central nervous system (CNS)
Summary
Lipid nanoparticles (LNPs) represent an effective platform for delivering small molecules, RNA, or DNA into target cells [1]. By changing lipid composition [6] and/or including short peptides [9] and ligands [10], one can modulate the biodistribution of the LNP in the body Despite these advances, targeting of LNPs to the brain tissue remains a challenge [11]. The peptide T7 consisting of seven amino acids (H-HAIYPRH-NH2) was identified via phage display [24] and has a high affinity (≈10 nM) for the transferrin receptor [24,25] This peptide does not compete with endogenous transferrin binding and has been used to successfully enhance drug delivery to brain tissue [15,22,24,25,26]. The careful choice of Dap and palmitic acid allows for the entire synthesis to be performed on solid support with no need for additional reactions after cleavage [27,28,29]
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