Nanoparticles: Promising Tools for the Treatment and Prevention of Myocardial Infarction

Figures & data

Figure 1 Overview of nanoparticle-based strategies for the treatment and prevention of myocardial infarction. Nanoparticles are capable of delivering therapeutic agents and nucleic acids in a stable and targeted manner, improving the properties of tissue engineering scaffolds, labeling transplanted cells and regulating cell behaviors, thus promoting the cardioprotective effects of traditional or novel therapies.

Table 1 NPs-Based Drug Delivery Systems for Treatment for MI Reported in the Last 7 Years

Material	Modification Method	Particle Size	Payload	Species and Model	Cardiac Therapeutic Effects and Assessment Method				Safety	Ref.
					Function and Hemodynamy	Necrosis and Fibrosis	Angiogenesis	Other Effects
Delivery of western drugs
PLGA	Modification with SS31 (a mitochondria-targeted peptide) and PEGylation	~54 nm	CsA	Rats; I/R (LAD for 30 min)	Recovery of heart rate and  ± dp/dtmax↑	Infarct size↓(Evans Blue/TTC dual staining);	↑(IF)	Recovery of ∆Ψm; production of mitochondrial ROS and apoptosis of H/R injured H9c2 cells↓; serum myocardial damage biomarker↓; better mitochondrial morphology		[^Citation25]
Soybean phosphatidylcholine and glycyrrhizinic acid salts		110±3nm	Celecoxib	Mice; LAD	LVEF, FS↑; expansion of chamber dimensions, LVEDV and LVESV↓ (E)	LV wall thinning and lumen dilatation↓ (HE staining)	↑(IHC)		No associated thrombotic events	[^Citation103]
Liposome		~60 nm	Methotrexate	Rats; LCA	LVIDD, LVISD and cardiac hypertrophy↓; EF↑(E)	Infarct size↓; cardiomyocyte hypertrophy↓; Collagen I/III↓(HE and Masson’s trichrome)		Inflammatory cells↓; ROS↓; expression of VEGF and adenosine receptors↑; cell death in the non-infarcted↓ (HE, IF); apoptosis↓(Western blot)	No clinical or laboratory toxicity in the animals	[^Citation102]
PLGA		~271nm	Pioglitazone	Mice and mini-pig; I/R (LAD for 30min/1h)	LVEDD, LVESD↓(E)	Infarct size, reperfused infarct size, and fibrosis↓(Masson’s trichrome)		Activity of cathepsin B↓; Ly6Clow monocytes and type 1 macrophages↓; type 2 macrophages, myocardium PPARγ DNA-binding activity↑; mortality↓;		[^Citation104]
Poly-lysine-PEG copolymer		~77nm	Exenatide	Rats; I/R (LAD for 30min)	LVEF, +dp/dtmax, and BP↑, LVEDP and HR↓(E, non-invasive BP Analyzer)	Histopathological alterations↓(HE)		Serum CK, LDH, and cTnT↓, GLP-1↑; cardial SOD and GLP-1 receptor↑, malondialdehyde↓;		[^Citation106]
PLGA		~159nm	Pitavastatin	minipigs, I/R (ligation of left circumflex coronary artery for 60min)	LVEF and FS↑ (E) LVESV↓(E)	↓(Masson-Trichrome)		Inhibition of monocyte/macrophages		[^Citation107]
PLGA		~200nm	Irbesartan	Mice; I/R (LAD for 30min)	LVEF,LVFS↑(E)			Inflammatory protease activity and Ly6C high monocytes recruitment↓		[^Citation187]
PEG-carboxymethyl chitosan		~68 nm	Insulin	Diabetes rats (induced by streptozotocin); I/R (LAD for 45min)		↓(TTC)		CK, LDH↓; NF-κB, SSAT↓, ODC↑		[^Citation188]
PEG-PLA	Conjugation with fibrin-targeting moiety clot-binding peptide (cys-arg-glu-lys-ala)	121.4±2.6 nm	Thymosin beta 4	Mice; I/R (LAD for 90min)	LVEDD, LVESD↓(E)		↑(IF)	Wt-1↑; CMs apoptosis↓	No toxicity	[^Citation189]
Delivery of plant-derived therapeutic agents (traditional Chinese medicine)
mPEG-PLA-TPGS		100–200nm	Tanshinone IIA	Mice; LAD	LVEDD, LVESD↓, LVEF, FS↑(E)	Heart weight to body weight ratio, scar circumference and fibrosis area↓(Masson’s trichrome)		Myocardial angiotensin II type 1 receptor, nuclear NF-κB p65, TNFα, TGFβ1, SMAD3, MMP-2, MMP-9, IL-1β, IL-6, MCP1 and IL-18 expression and apoptosis↓		[^Citation30]
Au		203.4 ± 4.72nm	Pe.EA	Mice; ISO-induced MI		Cardial necrosis and separation of myocardial fibers↓		Serum levels of TG, TC, LDL, ALT, AST, LDH and CPK↓; DNA damage↓		[^Citation50]
PLGA	Coating with PEG modified by IMTP, as well as SS-31 peptide (targeting to mitochondria)	~89nm	Resveratrol	H9c2 cell (hypoxia) Rats; I/R (LAD for 30min)	±dp/dtmax and LVESP ↑(E)	Infarct size↓(TTC)		LDH↓; uptake↑; ROS↓		[^Citation108]
SLNs	PEGylation and arginine-glycine asparagine modification	~110nm	Puerarin	Rats; LAD		Infarct size↓(TTC)				[^Citation109]
MSNs		100–150nm	Quercetin	Rats; I/R (LAD)	↑(E)	Infarct size↓(Masson’s trichrome)		Apoptosis and oxidative stress↓		[^Citation110]
Polymer		30–100nm	Curcumin	Rats; ISO-induced MI		Myocardial necrosis↓(HE staining)		CK, CK-MB, oxidative stress markers↓; serum levels of MMP2, MMP9, TNF-α, IL-6, IL-1α, IL-1β, MCP-1, and RANTES↓, local inflammation↓		[^Citation111]
PLGA		~194.82nm	Wogonin	Rats; ISO-induced MI		Infarct size edema, and necrosis↓(TTC, HE)		LDH, cTnT, and CK-MB, lipid peroxidation product, TNF-α, IL-1β, and IL-6↓; catalase, SOD, Nrf2 and heme oxygenase-1↑; myocardial inflammatory cells↓		[^Citation190]
Lipid NPs	PEGylation	~83.9 nm	Baicalin	Rats; LAD		Infarct size↓(staining/photographed)				[^Citation191]
Lipid-polymer hybrid NPs	Conjugation with distearoyl phosphatidylethanolamine-PEG	100–200nm	Salvianolic acid B and panax notoginsenoside	Rats; I/R (LAD for 45min)		Infarct size↓(TTC)			No toxicity	[^Citation192]
SLNs	Modification with PEG and MMP-targeting peptide	~130nm	Schisandrin B	Rats; partial LCA		Infarct size↓(TTC)				[^Citation193]
SLNs		~104.83nm	Flavonoid extract from Dracocephalum moldavica L.	Rats; I/R (LAD for 30min)		Infarct size↓(TTC); histopathological damage↓(HE)		Expression of LDH, CK, IL-1β and TNF-α↓, integrity of the myocardial membrane and myocardial fibers↑		[^Citation194]
Au		17–29 nm	Pro-anthocyanidin	Rats; ISO-induced myocardial injury				AST, ALT, cTnT and homocysteine in plasma↓		[^Citation195]
Delivery of small molecular inhibitors
Porous silicon	Functionalization with ANP	~180nm (Ref. 113)	3i-1000; OR C143 (a ERK1/2 inhibitor)	Rats; ISO-induced MI				ANP, BNP, COL1A1, IL-6 and OPN gene expressions↓; Hypertrophic signaling↓ (ERK signaling cascade)		[^Citation43, [^Citation113]
PLGA		~227nm	TAK-242	Mice; I/R (LAD for 30min)	LVEDD, LVESD↓(E)	Infarct size↓(Masson’s trichrome)		HMGB1,NF-κB↓; Neutrophils and Ly-6C high inflammatory monocytes↓		[^Citation112]
Poly(N-isopropylacrylamide) and N,N′-methylenebis(acrylamide)		~244 nm	Y-27632 and t-PA	Rats; I/R (LAD for 30min)	LVEF, FS↑(E)	Infarct size↓(Masson’s trichrome)		α-SMA level, cellular contractility, reduce stress fiber formation, and decrease CTGF expression↓		[^Citation196]
PLGA		~194nm	Mdivi1	Mice heart (Langendorff-Perfused); I/R (ischemia for 45min)		Infarct size↓				[^Citation197]
Delivery of growth factor and other regulatory molecules
PLGA; OR Crosslinked heparin polysaccharide		113.1 ± 5.2 nm (PLGA); OR 150–155nm (Heparin:VEGF 100:6)	VEGF	Mice; LAD	LVEF, LVFS, LVEDD and LVESD↑(E); LVIDD, LVISD↓(E)	Infarct size↓, wall thicknesses↑ (Sirius red and fast green staining)	↑(IHC)	Myocardiac water content↓; lymphangiogenesis↑; heart‐to‐body weight ratio and heart weight‐to‐tibia length ratio↓	No obvious toxicity in vivo	[^Citation26, ^Citation114]
Chitosan and fucoidan		<150 nm	VEGF or SDF-1	Rats; LAD	LVEF, SF↑(E)	Infarct size ↓(Masson’s trichrome)	↑(IF)	CMs proliferation↑(IF);		[^Citation115]
Gelatin NPs		180–255 nm	BIO and IGF-1	Rats; LAD	LVEF, FS↑; LVEDD, LVESD↓ (E)	CMs↑(HE)	↑(IHC)			[^Citation117]
Poly(ethylene argininylaspartate diglyceride)			TIMP-3/ FGF-2/ SDF-1α	Rats; LAD	FAC↑, LVESV, LVEDV↓(E)		↑(IF)	Preserved myocardial elasticity (MRI); CMs survival↑; apoptosis↓(IF); inflammatory↓		[^Citation118]
Delivery of other payloads
Polystyrene coated with iron oxide		230±35nm	Diallyl trisulfide (H2S donor compound)	Mice; I/R (LAD for 30min)	HR↓; EF, FS↑(E)				No detrimental effect on homeostasis in vivo at appropriate concentration	[^Citation15]
Au		14±3 nm	DNAzyme	Rats; LAD	±dp/dt, LVEF, FS↑(E)			TNF-α mRNA↓(qPCR)		[^Citation119]
PEG-poly oxymethyl estyrene		~40nm	2,2,6,6-tetramethyl piperidine-1-oxyl	Dog; I/R (LAD for 90min)	Infarct size↓(TTC)			Apoptosis↓; ventricular fibrillation ↓; coronary venous end-products of nitric oxide↓		[^Citation198]
Dodecafluoropentane		~250nm	Oxygen	Mice; LAD		Infarct size↓(TTC)				[^Citation199]
Lipid NPs	Modification with ANP	167.9±4.6nm	Adenosine prodrug	Rats; I/R (LAD for 45 min)		Infarct size↓(TTC)				[^Citation200]

Abbreviations: PLGA, poly(lactic-co-glycolic acid); NPs, nanoparticles; PEG, poly (ethylene glycol); i.v., intravenous injection; CsA, cyclosporine A; I/R, ischemia/reperfusion; LAD, left anterior descending ligation; ±dp/dtmax, the maximal rate of the increase (decrease) of LV pressure; TTC, triphenyltetrazolium chloride; IF, immunofluorescence; ∆Ψm, the membrane potential; ROS, reactive oxygen species; LV, left ventricular; EF, ejection fraction; FS, fractional shortening; ESV, end-systolic volume; EDV, end-diastolic volume; E, echocardiography; IHC, immunohistochemical staining; TEM, transmission electron microscope; LCA, left coronary artery ligation; LVISD, systolic LV internal diameter; LVIDD, diastolic LV internal diameter; PPAR, peroxisome proliferators-activated receptors; ESP, end systolic pressure; EDP, end diastolic pressure; BP, blood pressure; GLP, glucagon-like peptide; SOD, superoxide dismutase; SSAT, spermidine/spermine N’-acetyltransferase; ODC, ornithine decarboxylase; PLA, polylactide acid; TPGS, D-α-Tocopheryl PEG 1000 succinate; MMP, matrix metalloproteinase; MCP, monocyte chemoattractant protein; ISO, isoprenaline; Pe.EA, ethyl acetate fraction of Paeonia emodi; CPK, creatine phosphokinase; IMTP, ischemic myocardium targeted peptide; MSNs, mesoporous silica NPs; RANTES, regulated upon activation, normal T cell expressed and secreted; SLNs, solid lipid NPs; Nrf2, nuclear factor erythroid 2-related factor; ANP, atrial natriuretic peptide; COL1A1, collagen type I alpha 1 chain; IL, interleukin; OPN, osteopontin; t-PA, tissue-type plasminogen activator gene; HMGB, high mobility group protein; SMA, smooth muscle actin; CTGF, connective tissue growth factor; Mdivi, mitochondrial division inhibitor; BIO, 6-bromoindirubin-3-oxime; IGF, insulin-like growth factor; TIMP, tissue inhibitor of metalloproteinases; FGF, fibroblast growth factor; FAC, fractional area change; ↑, increased/upregulated; ↓, decreased/downregulated.

Table 2 NPs-Based Nucleic Acid Delivery Systems for Treatment for MI Reported in the Last 7 Years

Material and Modification Method	Particle Size	Payload	Species and Model	Delivery Method	Therapeutic Effects	Safety in vivo	Ref.
DNA/modRNA delivery system
Epoxide-derived lipidoid complex (C14-1138)	~155 nm diameter	eGFP modRNA	Rats, LAD; Pigs, embolic coil after balloon occlusion	Intramyocardial injection; ascending aorta (pig only)	eGFP expression↑	No obvious cytotoxicity	[^Citation122]
Bioreducible dendrimer polymer		HR1 (a plasmid)	Rats; I/R (LAD for 30min)	Infarct and peri-infarct area injection	LVEF, coronary artery stroke volume, CO, hemodynamic function↑(E); Fibrosis↓		[^Citation201]
miRNA delivery system
Heparin@PGEA	~180nm	miR-499 (alone or with pVEGF)	Mice; LAD	i.v.	LVEF/LVFS/LVIDD/LVIDS improvement; Infarct size, fibrosis and hypertrophy↓; Angiogenesis↑; Apoptosis↓	No evidence of toxicity	[^Citation123]
Hyaluronan-sulfate	~130 nm	miR-21 mimic	Mice; LCA	i.v.	LV posterior wall and LV mass; Collagen deposition ↓; Angiogenesis↑; TNFα↓, TGF-β and Socs1↑		[^Citation124]
PFBT core with a DSPE-PEG shell, conjugated with CPP	~110nm	miR-199a-3p	Rats; I/R (ligation for 1h)	Peri-infarct area injection; in shear-thinning hydrogel	EF↑; preserved LVESV; Scar size↓; Angiogenesis↑; Proliferation of CMs↑; Expression of HIF1α↑		[^Citation125]
Poly(amidoamine)-histidine	60nm	miR-214-3p, miR-194-5p, antagomiR-122-5p	H9c2 and primary cultured CMs		Expression levels of Bax, Bad, Caspase 3 and Caspase 9↓; Apoptosis↓; Cell viability↑		[^Citation127]
siRNA/ antisense oligonucleotide delivery system
Dendrigraft poly-L-lysine, decored with AT1R-targeting peptide, and PEGylated	~200nm	Anti-miR-1 antisense oligonucleotide	Mice; LAD	i.v.	Infarct size↓(Masson-Trichrome)		[^Citation130]
PMSNs, combined with PEI	100–200nm	CCR2 siRNA	Mice; LAD	Combined therapy: intramyocardial injection (MSCs) and i.v. (NPs)	Infarct size↓; Angiogenesis↑; Ly6C high monocytes/CD11b-positive monocytes↓	No obvious toxicity	[^Citation131]
A polymer–lipid hybrid material, combined with PEG–lipid conjugates	60–80nm	siSdf1, siMcp1	Mice; LCA after 10-week high-fat diet	i.v.	Preserved LV anatomy and function; Infarct size and fibrosis↓; Bone MSCs and leukocytes release↑(siSdf1)/↓(siMcp1); Inflammation of infarction area↓		[^Citation202]
Lipidoid NPs	50nm	CRMP2 siRNA	ApoE-/- mice; LCA	i.v.	M2 polarization↑; Inflammation, infarct size and fibrosis↓;(Masson’s trichrome) Post-MI heart failure and mortality↓		[^Citation203]
Lipidoid NPs		IFR5 siRNA	ApoE-/- mice; LCA	i.v.	MMP9/TIMP1↓; healing ↑; HF↓		[^Citation204]
Arginine-terminated generation 4 poly(amidoamine) (Arg-G4)	152.2±18.5 nm	PHD2 siRNA	Mice; LCA	Intramyocardial injection of Arg-G4-siRNA transfected MSCs	LVEF and LVFS; Infarct area↓; Survival↑		[^Citation205]

Abbreviations: eGFP, enhanced green fluorescent protein; PGEA, ethanolamine-modified poly(glycidyl methacrylate); PFBT, poly(9,9-dioctylfluorene-alt-benzothia-diazole); DSPE, 1.2-distearoyl-sn-glycero-3-phosphoethanolamine; CPP, cell-penetrating peptide; PMSNs, photoluminescent mesoporous silicon nanoparticles; PEI, polyethylenimine; MSC, mesenchymal stem cell; AT1R, angiotensin II type 1 receptors; Sdf1, stromal-derived factor 1; CRMP, collapsin response mediator protein; HR1, human Relaxin-expressing plasmid DNA with hypoxia response element 12 copies; IRF5, interferon regulatory factor 5; CO, cardiac output.

Table 3 Studies Combining NPs and Cell Therapy Reported in the Last 7 Years

Material of NPs	Modification and Drug Loading	Cell Type	Species and Model	Delivery Method	Cardiac Therapeutic Effects and Assessment Method				Safety	Ref.
					Function and Hemodynamy	Necrosis and Fibrosis	Angiogenesis	Other Effects
NP-ASCs combined system
PLGA	Loading of simvastatin	ASCs	Mice; LAD	i.v.	LVEF, LVIDD/LVISD↑(E)	LV fibrosis length, infarct size↓; scar area wall thickness↑; cardiac granulation tissue development and regeneration (Masson’s trichrome, IF)	↑(IHC)	Differentiation into SMCs and ECs↑; VEGF, IGF-1↑; apoptosis(TUNEL)↓		[^Citation17]
SPION		ASCs	Rats; LAD	Intramyocardial injection (with external magnetic field)	LVEF↑; LVEDV, LVESV↓(MRI)		↑(IF or IHC)	Levels of HIF-1α, VEGF, HGF, IGF-1↑; CMs apoptosis↓		[^Citation18, ^Citation162]
Fullerenol NPs		ASCs	Rats; LAD	Infarction border zone injection (in alginate hydrogel)	LVIDS↓LVIDD↓LVEF↑LVFS↑	MI size↓(Masson’s trichrome)		ROS↓(cell study)		[^Citation206]
Lipid-based NP emulsion	Loading of cyclosporine A	ASCs	Swine; I/R by LAD	Intracoronary injection	LVESV↓(MRI)	MI size↓(IF)	↑(IF)	ASCs survival↑(IF)		[^Citation207]
PLGA	Modification with mPEG; loading of melatonin	ASCs	Rats; I/R by LAD	Infarction border zone injection	LVEF↑			ASCs survival↑(bioluminescence imaging)		[^Citation208]
Au	Functionalization with amine compound	MSCs	Mice; cryoinjury	Extracellular matrix/ silk protein fibroin patches	Wall thickness↑(HE staining)	Infarct size and fibrosis↓(HE staining)		Retention and cell activity of MSCs on patches↑		[^Citation44]
NP-MSCs combined system
IONP		MSCs	Rats; I/R by LAD	Infarction border zone injection		MI size↓ Fibrotic tissue formation↓(Masson’s trichrome)	↑(IF)	Connexin 43↑(IF); Survival↑(TUNEL)		[^Citation164]
MagBICE2 (Feraheme NPs)	Conjugating with anti-CD45 and anti-MLC antibodies	Bone marrow-derived MSCs	Rats; I/R by LAD	i.v.		MI size↓(Masson’s trichrome)		Binding in heart↑(IF)		[^Citation160]
Silica-IONP	Loading of IGF	MSCs	Mice; I/R by LAD	Intramyocardial injection	LVEF and global longitudinal strain↑(E)	Cardiomegaly and fibrosis↓(HE, trichrome staining)		Survival and retention of MSCs↑; MCP1, VEGF, HGF↑; TGFβ↓	No toxicity in vivo	[^Citation161]
System of NP combined with other cell types
Silica-coated MIONs		EPCs	Rats; LAD	i.v. (followed by external magnetic field for 1h)	LV wall thickness↑, ventricular dilatation↓ (Masson’s trichrome)	Fibrosis markers↓; fibrosis area and infarct size↓ (Masson’s trichrome)	↑(IF)	Retention of EPCs↑; apoptosis↓(TUNEL)		[^Citation51]
Ferumoxytol NPs		CDCs	Rats; I/R by LAD	Coronary injection (with magnetic field for 10 min)	EF↑(E)		↑(counting)	Cell retention↑		[^Citation159]
Magnetic NP-containing liposomes		Multilayered ADRCs sheets	Mice; I/R by LAD	Injection in the ischemic heart	LVFS, LVEF↑(E)	Interstitial fibrosis↓(Masson’s trichrome)	↑ (IF)			[^Citation209]

Abbreviations: ASCs, Adipose-derived stem cells; IONP, iron oxide NPs; MIONs, magnetic IONP; SPION, superparamagnetic IONP; HGF, hepatocyte growth factor; EPCs, endothelial progenitor cells; CDCs, cardiosphere-derived stem cells; MagBICE, magnetic bifunctional cell engager; ADRCs, adipose-derived regenerative cells.

Table 4 NPs-Based Preventive Strategies for MI Reported in the Last 7 Years

Materials and Modifications	Particle Size	Payload	Species and Model	Therapeutic and Preventive Effects	Safety	Ref.
Primary prevention
PLA	~279nm (by SEM)	Aliskiren	Spontaneously hypertensive rats	BP↓; vasoactivity of mesenteric artery Collagen content in the aorta↓; Fibrosis of aortic tunica media↑ LV total NOS and neuronal NOS↑; endothelial NOS↓		[^Citation29]
Biscarbamate-crosslinked Gal-PEG-PEI NPs		AGT shRNA	Spontaneously hypertensive rats	BP↓; Heart hypertrophy↓; Myocardial ultrastructure improvement		[^Citation172]
PLGA		Propylene glycol alginate sodium sulfate	Rats; 8-week streptozotocin induced diabetic cardiomyopathy	LVEF, FS↑; LVISD, LVIDD↓ Myocardial morphology↑ Coronary microcirculation↑ Plasminogen activator inhibitor-1 expression in CMs↓; TNF-α, IL-1β, IL-6↓; NF-κb and AGEs/RAGE pathway↓; serum SOD and GSH↑		[^Citation210]
Hyaluronic Acid		Curcumin	Hypertensive, heterozygous rats	BP↓		[^Citation211]
Lipid NPs	65~75nm	ApoB siRNA	Lean rhesus macaque	LP(a) ↓		[^Citation212]
SLNs	180–220 nm	Candesartan cilexetil	Rats; oral fructose solution	BP↓; bioavailability↑		[^Citation213]
Avoiding AS development
Lipid mixture	60nm	Docetaxel	Rabbits; 8-week high-cholesterol diet	Atheroma area↓; levels of caspase 3, caspase 9, Bax, Bcl-2, MMP-2, MMP-9, TGF-β, NF-κB, TNF-α, IL-1β, IL-6, PCNA, vWF, collagen 1 and 3 in the aortic arch↓	No obvious toxicity	[^Citation9]
Leukosomes (liposome); Fabricated with membrane proteins of macrophages	108±2.3 nm	Rapamycin	Mice; 12-week high-fat diet	Plaque burden↓; proliferating macrophages in the aorta↓; MCP-1, IL-b1, MMP↓	Good tolerance	[^Citation90]
PEGylated SWNTs	5–6 nm	SHP1i	ApoE-/- mice; subcutaneous angiotensin II–infusing minipumps or 11-week high-fat diet	Plaque burden↓; lesional phagocytosis↑; inflammatory genes in lesional macrophages↓	Favorable safety profile	[^Citation177]
rHDL		TRAF-STOPs	ApoE-/- mice	Atherosclerotic plaques↓; leukocyte recruitment↓; Macrophages activation↓	No hepatotoxicity or functional hyposplenism	[^Citation178]
PEI	~45nm	ICAM1, ICAM2, VCAM1, Sel-E, Sel-P siRNAs	ApoE-/- mice; high-cholesterol diet and I/R injury (LAD for 45min)	Neutrophil and monocyte recruitment↓, matrix-degrading plaque protease activity↓		[^Citation187]
PLGA	214.3±0.6nm(SRM-NP); 216.9±0.6nm(PTX-NP)	Sirolimus (SRM-NP) or paclitaxel (PTX-NP)	Mini-pigs; temporary carotid closure and balloon angioplasty	Vascular stenosis and expression of PCNA↓, glycolysis and expression of HIF-1α in hypoxic ECs and SMCs↓		[^Citation214]
Lipid mixture	53.9–95.9nm	Curcumin	Rats; temporary carotid closure and balloon angioplasty	Neointimal formation↓;		[^Citation215]
PLGA (SPN) or liposome (LIP)	208±2nm (SPN); 174±2nm (LIP)	Methotrexate	Mice; 28-day high-fat diet	Intracellular lipids and oxidized LDL↓; RANTES, IL-1β, TNFα↓; IL-1α↑		[^Citation216]
PEG and sebacic acid	~100nm	D-PDMP	Mice; 8-week high-fat and cholesterol diet	AS plaque buildup, cholesterol ester crystal deposits, and fibrosis↓; FS↑ and cardiac hypertrophy↓ Oxidized LDL↓; changes of levels of genes associated with triglyceride metabolism		[^Citation217]
Lipid NPs	45 to 60 nm (Ref. 219)	Methotrexate or paclitaxel	Rabbits; high-cholesterol diet (with heterotopic heart transplantation and CsA administration in Ref. 218)	Coronary stenosis, macrophages infiltration↓; gene expression of TNFα, MCP1, IL-18, VCAM1, and MMP12↓; expression of IL-10 ↑; Macroscopic atheroma plaque area↓		[^Citation218,^Citation219]
Lipid NPs	60 nm	Carmustine	Rabbits; 8-week cholesterol diet	Lesion areas↓ Macrophages, FOXP3, IL-1β, LDL-R↓		[^Citation220]
Avoiding plaque rupture and thrombosis
PEG/PEI (Loaded into an E-selectin-targeting multistage microparticles)		miR-146a, miR-181b	ApoE-/- mice; 12-week western diet	Plaque size↓; Stabilization↑		[^Citation126]
Perfluorocarbon and excipient combined with alpha(nu)beta(3)-integrin antagonist		Fumagillin	Hyperlipidemic rabbits; 100-day cholesterol diet	Acute antiangiogenic effects		[^Citation182]
Albumin (linked to microbubbles)	~225.6nm	t-PA plasmid	Dogs; coronary bypass using the autoallergic saphenous vein	Thrombotic rate↓; Intimal thickness and proliferation of SMCs↓; t-PA and D-dimer contents in blood↑		[^Citation183]
Amphipathic, cationic peptide	~55nm	JNK siRNA	Mice; 14-week western diet	Barrier permeability and disruption↓; Foam cell formation, plaque necrotic area and Macrophages↓; Thrombotic risk↓; NF-κB and STAT3 expression↓	No toxicity in vivo	[^Citation184]
PEGylated and cRGD-coated liposomes	164.6±5.3 nm	t-PA	In vitro	Affinity↑; Fibrin clot lysis↑		[^Citation221]

Abbreviations: SEM, scanning electron microscope; NOS, nitric oxide synthase activity; AGT, angiotensinogen; GSH, glutathione; LP(A), lipoprotein(A); PCNA, proliferating cell nuclear antigen; vWF, von Willebrand factor; SWNTs, single-walled carbon nanotubes; SHP1i, SH2 domain-containing phosphatase-1 inhibitor; rHDL, recombinant high-density lipoprotein; TRAF-STOPs, tumor necrosis factor receptor associated factor (TRAF) 6; ICAM, intercellular cell adhesion molecule; VCAM, vascular cellular adhesion molecule; Sel, selectin; D-PDMP, D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol; LDE, lipid nanoparticle; cRGD, cyclic arginine-glycine-aspartic acid.

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