What if a drug carrier could find an atherosclerotic plaque, recognize its molecular signals, and release treatment only where disease is active? This review maps how nanoagents are being designed to make that precision approach possible.

Cardiovascular disease is the first killer of human health and causes at least thirty-one percent of global deaths. Atherosclerosis is one of the main reasons for cardiovascular disease. Oral drug therapy with statins and other lipid-regulating drugs is the conventional treatment strategy for atherosclerosis, but conventional strategies are constrained by low drug utilization and non-target organ injury problems.

Micro-nano materials, including particles, liposomes, micelles, and bubbles, have been developed for cardiovascular disease detection and drug delivery, specifically for atherosclerotic targeting treatment. These nanoagents are intended to deliver therapeutic agents to target atherosclerosis sites and release drugs intelligently and precisely, which could minimize potential adverse effects and be more effective in atherosclerotic lesions.

Atherosclerosis is a chronic disease characterized by the deposition of lipid in vascular tissues. It is the common pathological basis for ischemic cardiovascular disease, including stroke, coronary artery disease, cerebrovascular disease, and peripheral arterial disease.

Approximately seventeen point seven million people die from cardiovascular diseases each year, accounting for thirty-one percent of global deaths. The number of cardiovascular patients in China is now around three hundred thirty million, and the prevalence of cardiovascular disease is still rising.

Cardiovascular diseases continue to pose a significant public health challenge both in China and globally. Figure one maps atherosclerosis from initiation to progression and eventual arterial blockage. It shows how endothelial dysfunction, LDL accumulation, macrophage and PBMC involvement, smooth-muscle-cell changes, necrotic-core formation, and thinning of the fibrous cap contribute to plaque evolution.

The final panels connect fibrous-cap rupture with local inflammation, thrombus formation, and possible vessel obstruction, making clear why plaque biology matters for vascular disease. There are two main clinical treatments for atherosclerosis: oral medications such as statins, and, for advanced atherosclerosis with a stenosis rate greater than seventy-five percent, angioplasty and stenting, especially in the coronary arteries.

Restenosis and thrombosis remain major complications of stent implantation and significantly limit the long-term efficacy of stents, while oral drug strategies lack targeted therapy capability and have limited drug utilization rates. Nanoparticle-based targeting strategies are described as productive and promising in molecular imaging and treatment of atherosclerosis, a field known as theragnostic nanomedicine.

Nanoparticles can penetrate targeted plaques through injured endothelium or dysfunctional vessels, and nanocarriers can respond to abnormal lesion microenvironments such as reactive oxygen species, pH, enzymes, and shear stress. Nanocarriers are designed for swift and precise localization within an atherosclerotic lesion, followed by targeted drug delivery to the site in need.

The direction is to design nanocarriers with high specificity and high targeting. There are two primary approaches for delivering drugs to the lesion site using nanocarriers: enhanced permeability and retention, or EPR, and active targeting.

The EPR effect allows nanoagents to penetrate incomplete endothelium and accumulate in the atherosclerotic lesion, while active targeting uses surface modification to bind selectively to overexpressed receptors. Active targeting enhances both the aggregation ability and amount of nanoagents at the target lesion site, thereby improving therapeutic efficiency.

Figure two illustrates how nanocarriers can target an atherosclerotic plaque, shown as particles binding to endothelial markers including VCAM-one, ICAM-one, integrin, and E-selectin. The schematic places these interactions within the vessel lumen and intima, alongside foam cells, macrophages, dendritic cells, oxidized LDL, and structural components such as collagen and elastin.

It matters because it connects active molecular targeting with localized delivery to inflamed plaque tissue, where endothelial permeability and immune-cell activity are altered. The vascular endothelium serves as a barrier between the blood and the vascular wall and maintains physiological homeostasis of the vasculature under normal conditions.

During atherosclerosis development, the vascular endothelium is impaired by continual stimulation from immune responses, pathogenic organisms, and dysfunctional hemodynamics. This leads to an increase in adhesion molecules such as vascular cell adhesion molecule-one, intercellular adhesion molecule-one, E-selectin, and P-selectin.

These highly expressed adhesion molecules could be used as potential targets for nanoagents. Figure three diagrams a two-step synthesis of VCAM-one-targeted nanoparticles. First, a cationic poly-beta-amino ester polymer combines with anionic plasmid DNA encoding interleukin-ten for ten minutes, forming a cationic nanoparticle; then a PGA-PEG-R coating, using either the VHPK peptide or L-cysteine, is added for five minutes.

The schematic matters because it shows how the surface coating incorporates the VCAM-one-targeting peptide, creating NP-VHPK for delivery to inflammatory endothelial cells. Sun and colleagues coupled a VCAM-one-targeting peptide and the microRNA inhibitor anti-miR-seven-twelve to a DNA vector with complementary sequences modified on the surface of gold nanospheres.

That system selectively delivered anti-miR-seven-twelve to mouse aortic endothelial cells with elevated VCAM-one expression to inhibit atherosclerotic plaque formation. Distasio and colleagues synthesized a polyglutamic acid coating containing polyethylene glycol and the VCAM-one-specific targeting peptide VHPK, then used poly-beta-amino ester and DNA plasmid solutions to prepare nanoparticles.

Applying the targeting coating produced VCAM-one-targeting nanoparticles called NP-VHPK. Macrophages play an important role in all stages of atherosclerotic lesion development, from formation to plaque rupture. Nanoparticles carrying lipid-lowering drugs, anticoagulant drugs, small interfering RNA, DNA plasmids, and other therapeutic agents can target macrophages.

In atherosclerotic lesions, macrophages accumulate in the vessel wall through scavenger receptors such as CD36, lectin-like oxidized low-density lipoprotein receptor-one, and macrophage scavenger receptor-one. CD36 plays crucial roles in lipid metabolism, adhesion of anionic biomolecules, lipid uptake, and the development of atherogenesis, making it a common target for macrophage-directed therapy.

Nie and colleagues prepared liposome nanoparticles from phosphatidylcholine and KOdiA-PC. In low-density lipoprotein receptor-deficient mice, the nanoparticles selectively targeted and bound macrophages in atherosclerotic lesions through CD36 receptors.

Figure four schematically shows a CD36-targeted liposome, labeled a nanovesicle, moving from the arterial lumen into the arterial intima. Its phosphatidylcholine membrane displays CD36 ligands, while the diagram indicates uptake of both oxidized LDL and nanovesicles by macrophages or foam cells.

This matters because macrophage accumulation and lipid loading contribute throughout atherosclerotic lesion development, making receptor-targeted nanoparticles a way to deliver therapeutic cargo specifically to these cells. During atherosclerosis development, monocytes infiltrate the endothelium and differentiate into macrophages by taking up oxidized lipids deposited within the arterial wall.

These macrophages secrete inflammatory factors such as tumor necrosis factor alpha, interleukin-six, and interleukin-one beta, triggering inflammatory responses that promote further progression of atherosclerosis. Inflammatory cytokines can be regulated by introducing anti-inflammatory agents into the macrophage cytoplasm or by reducing inflammatory gene expression through RNA interference, or small interfering RNA.

Antioxidant nanoparticles were internalized efficiently and rapidly by macrophages and vascular smooth muscle cells, while inflammation, macrophage apoptosis, foam-cell formation, and atherosclerosis development were inhibited in the reported experiments. Collagen is a major component of the extracellular matrix and influences the strength and integrity of the fibrous cap during atherosclerosis development.

A peptide sequence with high affinity for type four collagen was identified through phage display investigations, and type four collagen is highly expressed at sites of vascular injury. More than fifty percent of the lesion basement membrane is composed of type four collagen, making collagen-targeting peptides on nanoparticle surfaces an effective strategy for targeting atherosclerotic plaques.

A collagen four-targeting nanoparticle containing interleukin-ten had anti-inflammatory effects on macrophages in vivo and in vitro, and the particles could prevent vulnerable plaque formation by increasing fibrous-cap thickness and reducing necrotic cores. Platelets possess coagulation and hemostatic functions essential for maintaining physiological homeostasis and repairing vascular damage, but they can also participate in inflammatory responses that promote atherosclerosis formation.

Studies found elevated platelet adhesion to the vessel wall at atherosclerotic lesion sites, so platelets could be a potential target for targeting atherosclerosis. Functionalized superparamagnetic iron oxide nanoparticles were designed to bind activated platelets or P-selectin, and they showed specific binding affinity toward activated platelets in the bloodstream for magnetic resonance imaging of lesions.

A limitation is that P-selectin is also expressed on inflammatory endothelial cells, which challenges the specificity of nanoparticle binding to platelets. Further investigation is therefore warranted. Efficient delivery and intelligent targeting of drugs are critical for atherosclerosis treatment.

Nanoagents have therefore been designed to respond to abnormal lesion-site microenvironments, including micro-acidity, high shear stress, overexpressed enzymes, and reactive oxygen species. Small-molecule drugs are encapsulated within nanocarriers through chemical or physical reactions, and the nanocarriers maintain structural integrity in normal tissues.

At the lesion site, specific stimuli trigger nanocarrier depolymerization and subsequent drug release, mitigating systemic toxicities associated with small-molecule therapeutics. Nanoagents can also respond to exogenous stimuli such as light and magnetic fields, or to multiple stimuli, to enhance efficacy for atherosclerosis.

Figure six illustrates how smart nanoagents target atherosclerotic lesions by sensing abnormal local conditions. On the left, endogenous stimuli include high shear stress, reactive oxygen species, enzymes, and acidic conditions; on the right, external triggers include magnetic fields, near-infrared light, and ultrasound.

The legend links these stimuli to responsive nanoagents and shows their placement among endothelial cells, vascular smooth muscle cells, leukocytes, macrophages, foam cells, T lymphocytes, and oxidized LDL, highlighting the potential for stimulus-controlled drug delivery. High reactive oxygen species levels lead to increased oxidized lipoproteins, endothelial dysfunction, DNA damage, leukocyte migration and differentiation, vascular smooth muscle cell proliferation, and elevated matrix metalloproteinases.

Because atherosclerotic diseased tissues have a high reactive oxygen species environment, researchers have explored various reactive-oxygen-species-responsive drug carriers. These carriers are typically constructed using polymers containing sulfur, selenium, or tellurium, phenylboronic acid ester, and co-administered photosensitizer reactive-oxygen-species-sensitive structures.

Figure eight shows how ROS-responsive filamentous hydrogels, or FM-depots, transform when oxidation increases their hydrophilicity: the filaments bud into drug-loaded spherical micelles. Across hydrogen peroxide concentrations, the particle diameter and polydispersity remain relatively consistent, while the photographs and thirty-day release curves show hydrogen-peroxide-dependent drug release.

In ApoE-knockout mice, aVD-loaded FM-depots are also associated with Foxp3-positive regulatory T-cell responses in lymph nodes and spleen, supporting oxidation-triggered delivery in inflammatory settings. During hydrogen peroxide oxidation, spherical drug-loaded micelles are released.

Their diameter and polydispersity index are less affected by hydrogen peroxide concentration, but drug-release efficiency depends on oxidant concentration. The drug-loaded hydrogel therefore sustainably releases drugs under oxidation conditions.

After subcutaneous injection into ApoE-deficient mice, vitamin D three-loaded filamentous-micelle depots maintained high levels of Foxp three-positive regulatory T cells in lymphoid organs and atherosclerotic lesions for several weeks. The acidic cellular microenvironment at sites of inflammation is well established.

Macrophages at atherosclerotic plaques phagocytose large amounts of oxidized low-density lipoprotein, leading to lactic-acid accumulation and further aggravating local acidity. Human atherosclerotic plaques exhibited a pH range of six point five to eight point five, while rabbit plaques ranged from five point five to seven point five.

Macrophage lysosomes measured a pH of four point seven to four point eight. The weakly acidic microenvironment of atherosclerotic lesions, with pH six point zero to six point eight, and the acidic environment of macrophage lysosomes, below pH five point zero, can be exploited for precise atherogenic-response therapy.

Various pH-responsive nanoagents have been designed and constructed, including systems initiated by covalent bonds, intermolecular forces, and physical structures. Anti-microRNA-thirty-three was loaded onto a nanocarrier with a cationic shell composed of polyethylene glycol chains modified by the peptide ligand cRGDfK, producing pH-responsive RAAM nanoparticles.

The anti-microRNA-thirty-three nanotherapeutics promoted reverse cholesterol transport and modulated adaptive immunity by regulating macrophage polarization and T-cell differentiation. After intravenous administration, RAAM nanoparticles accumulated in atherosclerotic plaques and associated cells of ApoE-deficient mice through passive and active targeting, then released anti-microRNA-thirty-three molecules in endolysosomes after endocytosis.

HRRAP nanoparticles released all-trans retinal and rapamycin together in response to abnormal pH, while the two agents reduced reactive oxygen species and lipid peroxidation, reduced inflammation, and inhibited macrophage and smooth-muscle-cell proliferation. HRRAP nanoparticles specifically accumulated in atherosclerotic plaques in apolipoprotein E-deficient mice and remarkably inhibited atherosclerosis progression.

Figure twelve summarizes both the construction and intended action of the anti-miR-thirty-three nanoparticles. In panel A, self-assembly combines an AcCD core, cationic material, lecithin, anti-miR-thirty-three, and PEG-based components, including the cRGDfK targeting ligand, to form RAAM nanoparticles.

Panel B depicts these particles targeting an atherosclerotic plaque, where the proposed treatment supports cholesterol efflux and shifts lesional immune responses, including macrophage polarization and T-regulatory-cell activity. Many enzymes involved in atherosclerosis formation, including matrix metalloproteinases, hyaluronidases, and cathepsins, can serve as stimulators and targets for drug delivery and controlled release.

Matrix metalloproteinases and hyaluronidase are the most extensively researched stimulators and targets, with matrix metalloproteinase thirteen, matrix metalloproteinase two, and matrix metalloproteinase nine listed as common target metalloproteases. Cathepsin B has significantly higher activity in unstable plaques than in stable plaques and may be used as both a target and a stimulator of atherosclerosis.

The described design confers hyaluronidase responsiveness and inflammatory macrophage targeting. The results showed that mesoporous silica nanoparticle nanocarriers had high loading efficiency, greater than twenty percent, and excellent enzyme responsiveness.

In vitro experiments confirmed targeting and anti-inflammatory effects of SIM-at-HA-MSN, together with low cytotoxicity and good hemocompatibility. Animal studies revealed prolonged plasma retention time and favorable in vivo biocompatibility of SIM-at-HA-MSN.

The therapy schematic proposes long circulation, hyaluronidase-responsive release, CD44-mediated macrophage targeting, anti-inflammatory activity, and reduced foam-cell formation near the vascular wall. This matters because the design links controlled delivery with several processes involved in atherosclerosis management, while the paper reports enzyme responsiveness, low cytotoxicity, good hemocompatibility, and prolonged plasma retention.

RAP-at-T slash R nanoparticles were designed to deliver rapamycin for atherosclerosis treatment and selectively target lesions by binding to alpha-v-beta-three overexpressed in inflammatory vascular endothelial cells. In vitro experiments showed that cathepsin K stimulation accelerated rapamycin release from the nanoparticles, significantly inhibiting oxidized low-density-lipoprotein phagocytosis and cytokine release from inflammatory macrophages.

The nanoparticles prolonged blood retention and increased accumulation in atherosclerotic lesions. RAP-at-T slash R nanoparticles significantly impeded atherosclerosis development and suppressed both systemic and local inflammation in ApoE-deficient mice.

Figure fifteen schematically shows how RAP@T/R nanoparticles are assembled from a CTSK-sensitive PLGA-peptide-PEG component, an integrin-targeting PLGA-PEG-cRGD component, and RAP. The particles target αvβ3 on inflammatory vascular endothelial cells, accumulate at atherosclerotic sites, and respond to CTSK and the acidic local environment to release RAP.

The proposed outcome is reduced OxLDL endocytosis, inflammatory cytokine release, and macrophage proliferation, thereby attenuating inflammation and atherosclerosis. As atherosclerotic plaques develop, luminal narrowing occurs, increasing fluid shear and wall shear stress at the lesion site within the vessel.

Normal wall shear stress ranges from one to ten dynes per square centimeter, whereas vulnerable plaque vessels reach thirty-one point ninety to one hundred thirty-six point zero nine dynes per square centimeter. Abnormal shear stress can act as a stimulating and targeting factor, triggering local drug delivery and release at the plaque lesion.

Many shear-responsive micro-nanoparticles mimic platelet structure, with drug release primarily attributed to carrier deformation or degradation under high shear conditions. Shear-activated nanoparticle aggregates loaded with tissue-type fibrinogen activator disintegrated into individual nanofractions under abnormally high fluid shear stress and induced rapid clot lysis in mice.

Exogenous-stimuli-responsive nanoagents are primarily inorganic nanoparticles used for in vitro diagnosis of atherosclerosis. They can be activated by light, ultrasound, and magnetic fields. These nanoagents respond to specific exogenous stimuli for imaging and are detected by corresponding devices.

Some inorganic nanoagents combine imaging with diagnostic integration, including gold nanoparticles, ions nanoparticles, and copper sulfide nanoparticles. Combining these inorganic nanoparticles with organic counterparts can enable drug delivery while simultaneously fulfilling the diagnostic imaging function of the inorganic nanoparticles.

The review’s central message is that effective atherosclerosis nanotherapy combines lesion targeting with stimulus-responsive release, potentially improving drug delivery while reducing effects on non-targeted tissues. The evidence is promising, but many approaches remain under investigation.