Table 2.

Nanoparticle strategies for the delivery of nucleic acid therapies to the atherosclerotic plaque.

Therapeutic Agent	Nanoparticle	Key nanoparticle materials	Size/Charge	Loading capacity (LC) and loading efficiency (LE)	Route of delivery	Injected dose	Model	Targeting strategy	Key Findings	Reference
VCAM1, ICAM1 and 2, E− and P-selectin siRNA to silence the gene expression of the cell adhesion molecules	Polymeric Nanoparticle	7C1 compound synthesised by reacting C15 epoxide-terminated lipids with PEI600	45 ± 16 nm	N/A	IV injection	3 mg/kg of siRNA in 10 μL/g body weight. Injected days 1 and followed by weekly injections	ApoE−/− mice	N/A	Decrease in leukocyte recruitment and plaque inflammation Reduction in necrotic core and lesion size Increase in fibrous cap thickness.	[98]
miR-146a and miR-181b	Polymeric Nanoparticles encapsulated in silicon microparticles	PEG/PEI complexes with miRNAs	Not specified	N/A	IV injection	15 μg of miRs in 100 μL, bi weekly for 12 weeks	ApoE−/− mice	Thioaptamer (ESTA) binding to E-selectin	∼60% and ∼50% decrease in lesion area in aorta compared to the control group when treated with NPs containing miR-146a and miR-181b respectively	[101]
miR-146	Superparamagnetic iron oxide nanoparticle (SPION)	Iron oxide	72.7 nm/−21.8 mV	275 strands per SPION	IV injection	10 mg/kg of Fe and 1.5 mg/kg of miRNA, twice a week for 3 weeks	ApoE−/− mice	Scavenger receptor class A (SR-A) mediated cellular uptake	Less toxicity due to being a non cationic nanomaterial Downregulation of genes related to the NF-κB pathway ∼30% decreased lesion areas in the aorta and aortic roots of treatment mice compared to the model mice	[107]
CCR2 siRNA	Polymeric Nanoparticle	Dextran	13.3 nm	N/A	IV injection	0.5 mg/kg	ApoE−/− mice	N/A	Significant reduction in inflammatory gene expression at the inflammation site.	[99]
CCR2 siRNA	Lipid Nanoparticle	C12-200 lipid, DSPC, cholesterol, PEG-DMG	70–80 nm	LE = 95%	IV injection	0.5 mg/kg, twice a week for 3 weeks	ApoE −/− mice	N/A	82% decreased macrophage number in atherosclerotic plaque in treatment compared to control	[102]
Anti-miR-712	Lipid Nanoparticle	DOTAP, DSPE-PEG2k, HSPC and cholesterol	167 ± 40 nm 44 ± 8 mV	LE = 95%	IV injection	1 mg/kg of anti miR-712 in 150 μL, injected at day 0, 3, 7, 10 and 14	ApoE−/− mice	VCAM-1 targeting peptide (VHPKQHR) binding to VCAM-1	Treatment group had a ∼66% reduced plaque size compared to the treatment group	[103]
Anti-miR33	Core-shell nanoparticle	Core: acetylated α−cyclodextrin Shell: PEG chains decorated with targeting moieties	147.5 ± 2.1 nm 9.9 ± 0.1 mV	LE = 88.1 ± 2.2%	IV injection	2 mg/kg, 2 injections first week followed by weekly injections for 2 months	ApoE−/− mice	cRGDfK peptide binding to αvβ3 integrin	Reduced macrophage population and matrix metalloproteinase-9 expression in plaques ∼64% reduction in total plaque area in treatment compared to the model	[105]
VE-cadherin siRNA	Liposome	POPC, SAINT-C18, Cholesterol, DSPE-PEG2000, and DSPE-PEG2000-Mal	106 ± 48 nm 3.8 ± 5 mV	LE = 71% ± 15	IV injection	10 μmol of total lipids/kg containing siRNA	HUVEC and HAEC for specificity and efficacy Male C57bl/6OlaHsd mice for PK	anti-E-selectin and anti-VCAM-1 antibodies binding to E-selectin and VCAM-1	Liposomes with anti-VCAM-1 antibodies showed increase in uptake of siRNA by HUVEC and HAEC compared to the anti-E-Selectin antibodies Downregulation of VE-cadherin mRNA by 60% and protein expression by 50% (HUVEC) and 25% (HAEC)	[100]
mTOR siRNA	Cerium oxide nanowire	Cerium oxide	146.4 ± 10.8 nm −12 ± 0.5 mV	LE = 70.6%	IV injection	0.5 mg/kg of siRNA	ApoE−/− mice	Stabilin-2-specific peptide (S2P) (CRTLTVRKC) binding to Stabilin-2	Higher uptake of S2P-PEGylated CeO2-NW in vitro and greater silencing of the mTOR gene compared to the CeO2-NW. In vivo studies showed comparable blood half life of ∼9.3 h The S2P- CeO2-NW showed a marked decrease in the progression of atherogenesis by a decrease in the atherosclerotic lesions by 67.3% compared to rapamycin (blocks mTOR) which showed a decrease of 41.3%	[106]
Anti-miR-712 (with carrier DNA having a complementary seq)	Gold nanospheres	Gold nanoparticle	5, 10, 20, 50 nm	N/A	–	–	immortalized mouse aortic endothelial cells (iMAECs)	VCAM-1-binding peptide (VHSPNKKGGSKGC) binding to VCAM-1	Best AuNP accumulation rate in left carotid artery was for particle size of 5 nm and showed specific delivery of anti-miR712 into VCAM-1 overexpressing cells	[104]