The application of mesoporous silica nanoparticles in the improvement

Introduction

The World Health Organization (WHO) reported that in 2021, atherosclerosis (AS) was associated with approximately 19 million deaths annually, positioning it as one of the leading chronic diseases globally. In the United States, AS was a major contributor to cardiovascular diseases, including myocardial infarction (MI), heart failure, and stroke, with more than 50% related deaths each year.¹ AS underlies various arterial diseases, including ischemic stroke, heart attack, and peripheral arterial disease.^2,3 AS is closely associated with both aging and premature biological aging, as atherosclerotic plaques exhibit features of cellular senescence marked by reduced proliferation, cell cycle arrest, increased apoptosis, and elevated DNA destruction. These instances of cellular senescence play a significant role in the progression of AS.^4,5 Currently, pharmacological treatments focus on managing major risk factors, particularly hypercholesterolemia/hyperlipidemia and elevated blood pressure, using lipid-lowering and antihypertensive agents.

Various pharmacological agents used to inhibit the progression of AS, including antihyperlipidemic and antihypertensive drugs, often encounter challenges such as poor aqueous solubility and adverse effects like myopathy and hepatotoxicity. These limitations compromise systemic bioavailability and reduce therapeutic efficacy.^6,7 To address these challenges, several strategies have been explored, including the use of nanocarriers. Among various nanocarriers, mesoporous silica nanoparticles (MSNs) offer distinct advantages, including high physicochemical stability, biocompatibility, substantial drug loading capacity, tunable pore sizes, and ease of surface functionalization.^8,9 Compared to liposomes and dendrimers, MSNs demonstrate superior scalability and structural integrity, making them particularly suitable for oral drug delivery systems.^10–12

Recently, mesoporous silica has emerged as a promising carrier for oral drug delivery, particularly in enhancing the dissolution profiles of poorly soluble drugs.^13–15 These mesoporous materials possess nanoscale pores capable of accommodating drug molecules in a non-crystalline or amorphous state, thereby improving their solubility and dissolution rate.^16,17 The drug is encapsulated within the pores, adapting to their nanosize and leveraging their high surface area. Additionally, due to the confined space within the pores, the drug molecules are unable to arrange in a regular pattern to form a crystal lattice structure, leading to the formation of an amorphous form or semi-crystalline structures.^18,19 The high surface area of mesoporous silica further supports efficient drug loading. Moreover, oral toxicity studies have demonstrated the safety of silica-based carriers for oral drug delivery systems.^19,20 Accordingly, the MSN represents a promising strategy to enhance the bioavailability of antihyperlipidemic and antihypertensive drugs while minimizing their side effects, leading to the improvement of their efficacy, safety, and stability.

Significant attention has been given to the incorporation of antihyperlipidemic and antihypertensive drugs into MSNs.^21–23 The ability of MSNs to encapsulate and protect antihyperlipidemic and antihypertensive drugs, along with enhancing bioavailability, presents an innovative strategy in drug delivery systems.^17,24,25 However, despite extensive research on MSNs for drug delivery, there is a lack of review articles explicitly addressing their use in the delivery of antihyperlipidemic and antihypertensive drugs. While previous reviews have broadly explored the potential of MSNs in drug delivery, focused analyses of these two therapeutic classes remain limited in the current literature.

This review addresses the identified gap by presenting a comprehensive analysis of the use of MSNs to enhance the delivery and therapeutic efficacy of antihyperlipidemic and antihypertensive drugs. It begins with an overview of the structural and physicochemical properties of MSNs, followed by a detailed analysis of their application in the delivery of cholesterol-lowering and blood pressure-regulating drugs. Additionally, the review discusses the pharmacological mechanisms, in vitro and in vivo efficacy, and MSN-drug interactions.

Furthermore, this review underscores key challenges in the clinical translation of MSN-based therapies, including limited long-term safety data, a lack of Phase I/II clinical studies, regulatory uncertainties, and scalability issues in pharmaceutical manufacturing. It aims to elucidate the potential of MSNs in advancing cardiovascular therapy and to encourage further research and innovation in this emerging field.

Methods

This review compiled relevant literature from PubMed, Scopus, and Google Scholar using keywords such as “mesoporous silica nanoparticles”, “atherosclerosis”, “antihyperlipidemic”, and “antihypertensive.” After the removal of duplicates, titles and abstracts were screened for relevance, followed by full-text evaluations to assess methodological rigor and contribution to the review’s objectives. Studies emphasizing solubility enhancement, pharmacokinetic improvement, and therapeutic applications of MSNs in cardiovascular-related treatments were prioritized. The selection process was conducted collaboratively by the review team to ensure consistency and minimize the risk of selection bias.

Atherosclerosis

Cardiovascular diseases (CVDs) have remained the leading cause of global mortality, accounting for nearly 20 million deaths worldwide in 2021, which has established them as the primary cause of death in middle- and high-income nations for decades.²⁶ Atherosclerosis leads to the formation of plaques within blood vessels. This obstruction significantly contributes to the initiation and progression of cardiovascular diseases. The term “atherosclerosis” originates from the Greek terms “athero” (gruel or paste), which describes the characteristic hardened tissue appearance of atherosclerotic plaque.²⁷ This condition develops when fat accumulates in the bloodstream, leading to chronic inflammation and further exacerbation within the artery walls.²⁸

Atherosclerosis initiates with the deposition of low-density lipoprotein (LDL) in the subendothelial layers of arteries.²⁹ LDL adheres to extracellular matrix proteins exposed by activated endothelial cells and is then oxidized by reactive oxygen species (ROS), resulting in oxidized LDL (ox-LDL). Macrophages then internalize both LDL and ox-LDL through scavenger receptors to generate foam cells. Foam cells and macrophages, secrete numerous pro-inflammatory cytokines, including soluble cluster of differentiation 40 (CD40) ligand, interleukin-1 (IL-1), IL-3, IL-6, IL-8, and tumor necrosis factor-alpha (TNF-α). IL-1β, IL-6, and TNF-α induce the liver to synthesize C-reactive protein (CRP), a significant inflammatory biomarker. Endothelial cells play a crucial role in the production of atherosclerotic plaques, particularly when stimulated by dyslipidemia or hypertension. These cells enhance the transcription of nuclear factor-κB (NF-κB) and express adhesion molecules including E-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). In conjunction with ox-LDL, these adhesion molecules facilitate leukocyte migration past the compromised endothelium into the intima of the blood vessel, resulting in the production of additional pro-inflammatory mediators that extend the inflammatory response. Arterial smooth muscle cells react to chemoattractants, small soluble molecules that bind to leukocyte receptors and enhance their activity, produced by activated leukocytes like platelet growth factor. This reaction triggers smooth muscle cells to migrate from the tunica media toward the intimal layer, contributing to the structural formation of mature atherosclerotic plaques. T cells exhibit both preventive and detrimental functions in the development of atherosclerosis. T regulatory cells (Tregs) and Th-17 cells reinforce plaques by secreting anti-inflammatory cytokines and augmenting the fibrous cap, while T helper 1 (Th1) cells exacerbate atherosclerosis through the secretion of interferon-gamma and TNF-α. Platelets exacerbate plaque development by adhering to endothelial cells, secreting chemokines and adhesion molecules, and facilitating LDL oxidation and macrophage ingestion. Collectively, these processes sustain chronic inflammation and plaque development, which are key features of atherosclerosis.³⁰ Figure 1 illustrates the mechanism of atherosclerotic formation.

Figure 1 Illustrates the mechanisms of atherosclerotic plaque formation. Adapted from Szwed P, Gasecka A, Zawadka M, Eyileten C, Al. E. Infections as novel risk factors of atherosclerotic cardiovascular diseases: Pathophysiological links and therapeutic implications. J Clin Med. 2021;10(12):2539. Licensed under Creative Commons Attribution 4.0 International License (CC BY 4.0).30

Currently, pharmacological treatments primarily focus on effectively managing major risk factors such as hypercholesterolemia/hyperlipidemia and elevated blood pressure. Several regimens are widely used in managing those risk factors, such as lipid-modifying agents for hyperlipidemia risks and antihypertensive agents for uncontrolled hypertension risks.

Antihyperlipidemics

Mechanism of Action of Antihyperlipidemic Drugs

Hyperlipidemia disrupts lipid metabolism in the bloodstream, resulting in elevated lipid levels. Lipids in the body consist of unesterified cholesterol, triglycerides (TG), phospholipids, and proteins.³¹ Lipids are transported in the bloodstream as lipoproteins: chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Each type plays a distinct role in transporting cholesterol and triglycerides in the body. Hyperlipidemia is associated with numerous disorders, including atherosclerosis, which illustrates the importance of drugs that can reduce elevated lipid levels.³² Healthcare providers commonly utilize lipid-lowering therapies, such as statins, fibrates, bile acid sequestrants, cholesteryl ester transfer protein (CETP) inhibitors, proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, and ezetimibe, to prevent cardiovascular disease (CVD).³³ Moreover, the mechanisms of action of antihyperlipidemic drugs are illustrated in Figure 2.

Figure 2 Illustrates the mechanisms of action of antihyperlipidemic drugs. Adapted from Ferri N, Ruscica M, Fazio S, Corsini A. Low-density lipoprotein cholesterol-lowering drugs: A narrative review. J Clin Med. 2024;13(16):4582. Licensed under Creative Commons Attribution 4.0 International License (CC BY 4.0).34

Statin

Statins are primary lipid-lowering drugs that inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) in the liver, reducing the conversion of HMG-CoA to mevalonic acid, a key step in cholesterol production. The activate sterol-regulated binding protein-2 (SREBP-2) pathway increases LDL receptor expression and enhances liver uptake of apo-B-containing lipoproteins, leading to lower plasma lipid levels.^34,35 Examples of statins include fluvastatin, pravastatin, rosuvastatin, cerivastatin, lovastatin, simvastatin, and atorvastatin.³⁶

Cholesteryl Ester Transfer Protein (CETP)

CETP is a hydrophobic glycoprotein that facilitates lipid transfer; inhibiting its activity raises HDL levels and reduces CE concentrations in VLDLs and LDLs. Notable CETP inhibitors include torcetrapib, dalcetrapib, evacetrapib, and anacetrapib.³⁷ Fibrates, such as gemfibrozil and fenofibrate, act as agonists of peroxisome proliferator-activated receptors (PPARα), enhancing HDL production by diminishing CETP activity, which lowers triglycerides and VLDL production.³⁸

Bile Acid Sequestrants (BAS)

BAS are cationic polymeric that prevent the conversion of cholesterol into bile in the liver, thereby enhancing low-density lipoprotein (LDL) receptor activity and facilitating the clearance of low-density lipoprotein cholesterol (LDL-C). Cholestyramine, colestipol, and colesevelam are FDA-approved drugs used to treat hypercholesterolemia.³⁹ Due to side effects when combined with statins as well as BAS’s benefits for other conditions like diabetes, their clinical uses are being reevaluated.⁴⁰

Proprotein Convertase Subtilisin Kexin 9 (PCSK9)

The inhibitory effect of PCSK9 diminishes LDL receptor (LDL-R) degradation, enhancing hepatic absorption of LDL-C to lower LDL-C concentrations. Evolocumab and alirocumab are monoclonal antibodies that inhibit PCSK9, limiting its binding to LDL receptors in hepatocytes and so averting the degradation of LDL receptors mediated by PCSK9.⁴¹ Small interfering RNA (siRNA) therapy, such as inclisiran, blocks the production of PCSK9. Inclisiran is a type of siRNA made of two strands of RNA and linked to a sugar molecule called N-acetylgalactosamine (GalNAc), which helps it target the liver. Its main goal is to block the production of PCSK9.³⁴

Niemann–Pick C1-Like 1 Protein (NPC1L1) Inhibitor

Ezetimibe is an established inhibitor of the NPC1L1. Ezetimibe diminishes the hepatic cholesterol reservoir and enhances the expression of LDL receptors on hepatocytes, resulting in increased elimination of LDL cholesterol from the circulation.⁴² Bempedoic acid works by directly and competitively inhibiting an enzyme called ATP citrate lyase (ACL), reducing acetyl-CoA production and cholesterol synthesis in the liver.³⁴

Presenting profiles of approved anti-hyperlipidemic drugs currently available can be seen in Table 1.

Table 1 Antihyperlipidemic Drugs Profile

Antihypertensive

Mechanism of Action of antihypertensive Drugs

Numerous classes of antihypertensive drugs exist, each with distinct methods of action.⁵⁵ Most antihypertensive drugs influence the intrinsic hormonal or neurological systems that regulate blood pressure regulation and induce a vasodilatory effect. The initial category comprises diuretics, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs).⁵⁶

Diuretics

Diuretics are a diverse group of drugs that increase urine output.⁵⁷ Diuretics are classified by their mechanism of action and their effect site in the nephron.⁵⁸ Carbonic anhydrase inhibitors (eg, acetazolamide) act on the proximal tubule, reducing Na⁺ and HCO₃⁻ reabsorption, causing mild diuresis. Loop diuretics (eg, furosemide) act on the ascending loop of Henle, strongly inhibiting Na⁺ reabsorption, and are effective even with low GFR. Thiazide diuretics (eg, hydrochlorothiazide) act on the distal tubule, reduce Na⁺ reabsorption, and are used for hypertension and edema.⁵⁹

Calcium Channel Blocker (CCB)

CCBs work by blocking calcium movement at L-type voltage-gated calcium channels, leading to vasodilation.⁶⁰ Calcium channel blockers (CCBs) are divided into dihydropyridines (DHPs) and non-DHPs. DHP-CCBs are vascular-selective vasodilators, while non-DHP-CCBs are cardiac-selective, used for tachyarrhythmia, but decrease cardiac contractility and heart rate.⁶¹ Examples of DHP include amlodipine and nimodipine, while non-DHP examples are diltiazem and verapamil.^62,63

Angiotensin-Converting Enzyme Inhibitor (ACEI)

ACE inhibitors block angiotensin-converting enzymes therefore inhibit hydrolyzing angiotensin I to produce angiotensin II that promote vasodilator and lowers blood pressure.^64,65 Lisinopril is the most commonly used antihypertensive regimen worldwide.⁶⁶

Angiotensin II Receptor Blockers (ARBs)

ARBs inhibit the effects of angiotensin II by preventing it from binding to the angiotensin II type 1 receptor (AT1 receptor), thereby contributing to lower blood pressure.⁶⁷ Irbesartan, losartan, telmisartan, and valsartan are examples of ARBs.⁶⁸

Angiotensin Receptor-Neprilysin Inhibitor (ARNI)

The mechanism of action of ARNI entails the inhibition of both the angiotensin II receptor and the neprilysin enzyme (NEP), which inhibits atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP).⁶⁹ This dual inhibition mitigates the detrimental effects of the renin-angiotensin-aldosterone system (RAAS) and amplifies the advantageous effects of natriuretic peptides.⁷⁰ Sacubitril/valsartan is the first of the class of ARNI.⁷¹

Mineralocorticoid Receptor Antagonists (MRAs)

MRAs block mineralocorticoid receptors to counteract aldosterone’s harmful effects, improving fluid balance and protecting the heart, vessels, and kidneys from inflammation and damage.⁷² Some examples of MRAs are spironolactone and eplerenone.⁷³

Furthermore, the mechanism of action of antihypertensive medications is illustrated in Figure 3.

Figure 3 Mechanisms of action for antihypertensive drugs. Adapted from Kreutz R, Algharably E. Encyclopedia of Molecular Pharmacology. Springer; 2021. Permission conveyed through Copyright Clearance Center, Inc.74

Profiles of approved antihypertensive drugs can be seen in Table 2.

Table 2 Antihypertensive Drug Profile

Limitation of Current Drugs

These antihyperlipidemic and antihypertensive drugs exhibit poor water solubility, according to the data on their physical and chemical properties presented in Tables 1 and 2. Limited aqueous solubility can significantly impact the drug’s distribution inside the body,^93,94 thereby diminishing its bioavailability and rendering the prescribed dose ineffective.^95,96 To overcome this challenge, researchers have utilized various approaches to enhance the solubility of the active ingredient. Numerous chemical and physical techniques have been developed to improve drug solubility.⁹⁷

Examples of chemical approaches include manipulating salt formation through acid-base reactions to enhance drug solubility. However, salt formation improves solubility without necessarily decreasing the required drug dosage. Cocrystallization is another promising technique that enhances solubility and dissolution, and improves both the physical and chemical properties of drugs. Cocrystals are multicomponent crystalline structures composed of active compounds and a co-former that establish hydrogen and van der Waals interactions to produce crystals. The selection of an appropriate co-former and the quality of the co-crystal remain the primary challenges in this process.⁹⁸ Another approach is co-solvency, which involves the addition of a water-soluble solvent to reduce surface tension between water and the drug. However, this method can be restricted by uncontrolled solid formation and the incompatibility of numerous insoluble compounds with available co-solvents.⁹⁹

Various physical procedures, in addition to chemical approaches, frequently enhanced drug solubility. One such method is particle size reduction; as particle size decreases, the surface area available for interaction with the solvent increases.¹⁰⁰ Nonetheless, this approach can lead to aggregation and degradation of active materials due to physical or mechanical stress. Another approach involves altering the crystal habit via polymorphism. Polymorphism refers to the ability of a substance to crystallize in more than one distinct crystalline form. Despite having identical chemical compositions, several pharmacological polymorphs exhibit unique physicochemical properties. The amorphous form of a drug generally exhibits higher apparent solubility and faster dissolution rates compared to its crystalline form, primarily due to its higher free energy and greater molecular mobility.⁹⁹ Nonetheless, polymorphic transitions can lead to solid-state instability and clinical failure.¹⁰¹ In addition to these methods, mesoporous silica nanoparticles (MSNs) serve as an effective method by enhancing solubility and minimizing drug dosage without inducing adverse effects.

Mesoporous Silica Nanoparticles (MSNs)

Mesoporous silica nanoparticles (MSNs) represent an extensively developed nanotechnology for diagnostic and therapeutic applications. Current research predominantly focuses on the use of MSNs for the delivery of anticancer drugs. Compared to other methods, MSNs offer precise drug release due to their pore volume and large surface area. MSNs can increase the solubility of poorly water-soluble drugs while providing greater physical and chemical stability, thus increasing drug bioavailability and reducing drug dosage.¹⁰²

Characteristic of MSNs

The sol-gel process is the primary method for the synthesis of MSNs. The size, shape, and porosity of the resulting MSNs are influenced by several factors, including the choice of surfactant, the type of cosolvent and its volume ratio to water, the reaction temperature, and the stirring speed. The final morphology of the MSN core, which commonly adopts a spherical or rod-like structure, plays a crucial role in determining its in vivo behavior and physiological fate.¹⁰³ MSNs exhibit greater resistance to physical and chemical environmental changes compared to other delivery systems.¹⁰⁴ The material for MSNs primarily consists of silanol groups, which are biodegradable and biocompatible, thereby reducing the risk of side effects. Additionally, MSNs demonstrate stability across a wide range of pH values, temperatures, and hydrolysis reactions.¹⁰²

Synthesis Methods of MSNs

MSNs can be synthesized through various methods, with the sol-gel and surfactant-templating techniques being the most widely utilized. The sol-gel method typically involves the hydrolysis and condensation of alkoxysilanes under acidic or basic conditions, producing silica frameworks with tunable porosity.¹⁰⁵ This technique is straightforward, cost-effective, and highly suitable for surface functionalization.¹⁰⁶ However, conventional sol-gel methods often yield MSNs with broad particle size distributions, irregular morphology, and potential for agglomeration, which can compromise reproducibility and drug delivery performance.¹⁰⁷

Such inhomogeneity primarily arises from uncontrolled hydrolysis and condensation kinetics during the sol-gel process, which significantly affect nucleation and particle growth. Xu et al⁹ reported that base-catalyzed sol-gel processes commonly yield particles ranging from 50 to 200 nm, often accompanied by variability in pore structure and size, factors that contribute to inconsistent drug loading and release profiles. Recent advancements, including hydrothermally assisted sol-gel synthesis and hard-template approaches, have enabled the production of MSNs with narrower size distributions and improved structural uniformity, thereby expanding the method’s applicability for pharmaceutical use.¹⁰⁸

In contrast, the surfactant-templating technique utilizes structure-directing agents that self-assemble into highly ordered micellar or liquid crystalline phases.¹⁰⁹ Silica precursors such as tetraethyl orthosilicate (TEOS) condense around these templates to form well-organized mesoporous structures, allowing for precise control over pore size, particle morphology, and nanostructural consistency.¹¹⁰ Fujii et al¹¹¹ demonstrated that the use of surfactant-templating agents, specifically cetyltrimethylammonium bromide (CTAB) and sodium dodecyl sulfate (SDS), in combination with hard templates facilitated the synthesis of MSN with finely tunable structural properties, including pore size of approximately 12 nm, shell thickness ranging from 5 to 9 nm, and surface areas reaching up to 553 m²/g. This approach enabled a remarkably high ibuprofen loading capacity (3009 mg/g) and exhibited sustained-release behavior, underscoring the utility of this method for producing structurally optimized drug delivery carriers. Supporting evidence by Elimbinzi et al¹¹² further confirmed that surfactant composition could be strategically adjusted to achieve pore sizes around 43 nm and surface areas of approximately 209 m²/g. Collectively, these findings underscore the superior batch-to-batch reproducibility and architectural precision of surfactant-templated MSNs, making them especially suitable for pharmaceutical formulations requiring reliable in vivo behavior and consistent therapeutic outcomes.

Structure of MSNs

The hexagonal, honeycomb-like structure of MSNs creates tunnels with numerous uniform pores, providing various advantages, including the capacity to carry a higher amount of active substances.¹¹³ Additionally, MSNs coat their outer surface with silanol groups, allowing for various functionalizations. This uniform pore size contributes to consistent drug loading and distribution, thereby increasing the bioavailability of the drug in the body. Furthermore, due to the utilization of both internal and external surfaces, MSNs exhibit a large surface area. This large surface area facilitates a high drug-loading capacity, reduces diffusion resistance, and enables controlled drug release, ultimately allowing for a reduction in the required dosage.¹⁰²

Characterization of MSNs

Scanning Electron Microscopy (SEM)

Scanning Electron Microscopy (SEM) is an essential method for characterizing MSNs, providing comprehensive insights into their morphology, dimensions, pore architecture, surface characteristics, elemental composition, size distribution, porous structure, and surface modifications.¹¹⁴ SEM images also reveal details such as particle size distribution, shape (eg, spherical or rod-like), surface roughness, and pore architecture.¹¹⁵

Huang et al¹¹⁶ employed SEM to analyze the surface morphology of MSNs. The findings revealed that the particles predominantly possessed a spherical shape with a uniform size distribution, accompanied by hexagonal-symmetry patterns on their surfaces, signifying a well-ordered mesoporous structure (Figure 4a). Similarly, AbouAitah et al¹¹⁷ utilized SEM to analyze the structural morphology of MSNs, demonstrating a uniform spherical shape with a pronounced 3D dendritic mesoporous architecture and the absence of aggregation, signifying successful synthesis and excellent colloidal stability.

Figure 4 Characterization of mesoporous silica nanoparticles (MSNs) by electron microscopy: (a) scanning electron microscopy (SEM), (b) transmission electron microscopy (TEM). Reproduced from Huang X, Young NP, Townley HE. Characterization and comparison of mesoporous silica particles for optimized drug delivery. Nanomater Nanotechnol. 2014;4(1):1–15. Licensed under Creative Commons Attribution 3.0 International License (CC BY 3.0).116

Transmission Electron Microscopy (TEM)

Transmission Electron Microscopy (TEM) is a crucial technique for characterizing MSNs, offering high-resolution insights into their morphology, particle size, and well-ordered pore architecture, including hexagonal channels.¹¹⁸ It also allows for precise particle size measurement, which can be correlated with disc centrifuge data, and, like SEM, TEM analyzes structural features using thin-sectioned samples.¹¹⁹

Huang et al¹¹⁶ employed TEM to examine the internal structure and morphology of MSNs, revealing a hexagonal-symmetry pore configuration with a particle size of 105.66 ± 23.11 nm and a pore size of 2.13 ± 0.21 nm, signifying a well-ordered mesoporous framework appropriate for drug delivery applications (Figure 4b). Similarly, Arcos et al¹²⁰ utilized TEM to examine the morphology and internal architecture of MSNs, revealing that samples with differing surfactant/silica ratios displayed spherical morphology with poorly crystalline mesopores, lamellar outer structures characterized by a periodicity of 8.5 nm, and partially decomposed polygonal particles, demonstrating that composition and thermal treatment substantially influence the structural order and stability of the mesoporous framework.

Brunauer-Emmett-Teller (BET)

Brunauer–Emmett–Teller (BET) analysis is a standard method used to determine the specific surface area and pore size distribution of MSNs through nitrogen adsorption–desorption isotherms.¹¹⁵ These measurements are critical for understanding the suitability of MSNs for applications such as drug delivery and catalysis.¹²¹

AbouAitah et al¹¹⁷ reported that the MSNs demonstrated a substantial BET surface area of 380.1 m²/g and a considerable total pore volume of 0.772 cm³/g, signifying a well-structured mesoporous architecture commonly linked to type IV nitrogen adsorption–desorption isotherms, characterized by a steep uptake at relative pressures (P/P₀) of 0.4–0.9 and a distinct hysteresis loop resulting from capillary condensation (Figure 5). Kumar et al¹²² also conducted BET analysis and determined that the MSNs displayed an extraordinarily high specific surface area of 1193.19 m²/g, hence corroborating the existence of a highly developed porous structure.

Figure 5 Characterization of mesoporous silica nanoparticles (MSNs) by Brunauer-Emmett-Teller (BET). Adapted from Abouaitah K, Hassan HA, Swiderska-Sroda A et al. Targeted nano-drug delivery of colchicine against colon cancer cells by means of mesoporous silica nanoparticles. Cancers (Basel). 2020;12(1):1–30. Licensed under Creative Commons Attribution 3.0 International License (CC BY 4.0).117

Dynamic Light Scattering (DLS)

Dynamic Light Scattering (DLS) is frequently employed to ascertain the hydrodynamic diameter and size distribution of MSNs, offering insights into particle populations and agglomeration tendencies.¹²³ Despite its utility, DLS exhibits limitations in resolution, is inappropriate for highly concentrated or opaque samples, and relies on precise knowledge of solvent viscosity.¹¹⁵

Paris et al¹²⁴ conducted DLS studies on MSNs, revealing a peak particle diameter of around 100 nm, indicating a very homogeneous nanoscale distribution throughout the colloidal suspension. Guerrero-Flórez et al¹²⁵ employed DLS to characterize the seed MSNs, determining an average hydrodynamic diameter of around 65 nm, which suggests a uniform and well-dispersed colloidal suspension.

Zeta Potential (ZP)

Zeta potential (ZP) is commonly employed to evaluate the surface charge and colloidal stability of MSNs.¹¹⁵ ZP data, often acquired using electrophoretic light scattering, assess nanoparticle dispersion behavior, surface modifications, and aggregation tendencies while being influenced by parameters such as pH, ionic strength, and medium composition.¹²⁶

Attia et al¹²⁷ assessed the zeta potential of MSNs and determined an average value of –16.84 mV, signifying the existence of negatively charged surface groups and moderate colloidal stability in aqueous dispersion. Kumar et al¹²² measured the zeta potential of MSNs and determined a value of roughly –25 mV at pH 7.4, indicative of deprotonated silanol groups on the MSN surface. The presence of this negative surface charge signifies excellent colloidal stability and is characteristic of silica-based nanoparticles in neutral water conditions.

Safety Profiles of MSNs

MSNs have demonstrated excellent safety profiles in both in vitro and in vivo studies, reinforcing their potential for therapeutic applications. MSNs are widely regarded as biocompatible and biodegradable, breaking down into non-toxic orthosilicic acid, which is naturally eliminated through renal and hepatobiliary pathways.¹²⁸ Numerous preclinical investigations have confirmed their low immunogenicity, minimal hemolytic activity, and high cellular compatibility.¹²⁹

In a recent study, Cheng et al¹³⁰ demonstrated that rod-like MSNs induced minimal oxidative stress and did not cause significant tissue damage in both in vitro and in vivo models, suggesting their favorable biocompatibility under physiological conditions. Furthermore, degradation rates and clearance efficiency can be modulated by adjusting particle size, pore structure, shell porosity and surface chemistry.¹³¹ For example, Fiedler et al¹³² demonstrated that the degradation rate and clearance efficacy of MSNs can be precisely controlled by postsynthetic modulation of shell porosity, without altering particle size. Using mesoporous silica shell-superparamagnetic iron oxide nanoparticles (SPION) core nanoparticles in the J774.A1 macrophage cell line, they observed that the silica shell underwent substantial lysosomal degradation within three days, indicating favorable intracellular biodegradability. Moreover, extracellular dissolution occurred even more rapidly, supporting the potential for efficient clearance. Both environments exhibited consistent degradation kinetics, underscoring the predictability and tunability of MSN behavior in biological systems.

Despite these promising results, clinical translation remains limited, primarily due to regulatory uncertainties and challenges in achieving scalability.¹²⁸ Nevertheless, the current body of evidence strongly supports the biosafety and pharmacokinetic manageability of well-engineered MSNs, highlighting their strong potential for safe integration into clinical drug delivery systems.⁹

Effect of MSNs on Dissolution and Bioavailability Enhancement

MSNs are recognized as next-generation pharmaceutical carriers due to their capacity to improve therapeutic efficacy by increasing water solubility and bioavailability. The ability of MSNs to increase drug solubility and dissolution rate is attributed to their nanoscale pores, which facilitate the transformation of crystalline molecules into amorphous form. The enhancement of drug solubility is supported by several distinctive characteristics of MSNs, including a high specific surface area, large pore volume, appropriately sized molecular pores, a well-organized pore structure, and the presence of surface silanol groups capable of interacting with various pharmacological compounds. Additionally, the wettability and porosity of hydrophobic drugs loaded into ordered MSNs can be enhanced.^102,133

MSNs have demonstrated significant potential to improve the oral bioavailability of poorly soluble drugs by enhancing drug dissolution rate and permeability. The porous structure of MSNs provides a high surface area for drug loading, thereby maximizing the contact between the drug and the surrounding medium and promoting faster dissolution. Moreover, MSNs can be constructed to enable controlled drug release by increasing the diffusion resistance, thereby improving drug absorption and ultimately allowing for dose reduction.^134,135

Effect of MSNs on Pharmacological Activity

As a drug delivery system, MSNs significantly increase pharmacological activity by enabling targeted drug delivery to specific tissues, providing controlled drug release over time, increasing bioavailability, and frequently allowing for reduced dosage requirements due to their large surface area and adjustable pore size. Targeted drug delivery using MSNs provides an efficient and safe treatment approach by concentrating the drug at the site of action while minimizing adverse effects on nearby healthy tissue, thereby improving therapeutic efficacy and potentially reducing side effects.¹³⁶ Safat et al¹³⁷ compared the cholesterol-lowering effect of Cynara scolymus (CS) extract loaded into Santa Barbara Amorphous-15 (SBA-15) MSNs (T group) with extract administered alone (CS group). The group of rats receiving the Cynara scolymus extract – SBA 15 formulation significantly lowered triglyceride (TG), total cholesterol (TC), and VLDL compared to the group treated with Cynara scolymus extract alone, indicating improved drug delivery in group T. In another study, Jia et al¹³⁸ evaluated the in vitro antitumor effect of paclitaxel. A higher antitumor effect was observed for paclitaxel incorporated into MSNs, as reflected by a lower eqn value, indicating a lower concentration needed to inhibit 50% of cancer cell viability. Furthermore, paclitaxel-loaded MSNs induced a higher apoptotic effect on MCF-7 cells compared to paclitaxel alone.

Antihyperlipidemic and Antihypertensive Drugs Loaded MSNs

Therefore, based on the discussion above, MSNs represent a promising strategy to address the poor water solubility of antihyperlipidemic and antihypertensive drugs.¹⁰² Many studies have shown positive results for using MSN technology in creating drugs to lower blood pressure and cholesterol, as summarized in Table 3.

Table 3 Previous Studies of Antihyperlipidemic and Antihypertensive-Loaded MSN

Dissolution

Dissolution is the process in which two phases combine to form a new, homogenous phase known as a solution.¹⁵⁴ In the pharmaceutical field, the term refers to the quantity of drug that dissolves per unit time under standardized conditions, which include defined interfaces between the liquid and solid phases, controlled temperature, and composition of the solvent. Dissolution testing is an essential quality control assessment for pharmaceutical dosage forms and is widely utilized as a prediction instrument for evaluating drug bioavailability.¹⁵⁵ The dissolving characteristics of a drug significantly affect its pharmacological efficacy, rendering it a critical factor in drug development and formulation.¹⁵⁶

The dissolution studies conducted by Bharati et al in 2024 utilized a USP type II apparatus with distilled water, hydrochloric acid, and phosphate buffer.¹⁴² The mesoporous silica loaded with efonidipine hydrochloride ethanolate (EFE-loaded MSNs) showed a 3.54-fold and 3.02-fold increase in the dissolution rate when tested in distilled water and phosphate buffer (pH 6.8) containing 0.05% w/v sodium lauryl sulfate (SLS), respectively. The high surface area of the mesoporous silica positively influenced the dissolving rate, in contrast to efonidipine hydrochloride ethanolate (EFE), which exhibited a lower dissolution rate across all three media. Furthermore, Farooq et al (2016) conducted ex vivo real-time release tests to examine the release profiles of the control and magnetic nanoparticles (MNPs).¹⁴⁹ The results show that MNPs with sodium nitroprusside (SNP) rapidly release 61.93% within the first 20 minutes. The peak relaxation of 64.16% occurred at 35 minutes; the highest relaxation reached 77.08% at 125 minutes. In a study by Kiwilsza et al, a design suitable for class II BCS active pharmaceutical ingredients (APIs) was used.¹³⁹ The results indicated that the crystalline nifedipine (NF) reached only approximately 30% after 700 minutes, while the encapsulated NF exhibited a significantly higher dissolution rate, achieving 60%, which is 83 times more than the crystalline NF.

In vitro Studies

Hypertension and dyslipidemia are major contributors to the development of atherosclerosis. However, the poor water solubility of drugs used to manage these conditions can hinder their absorption and therapeutic efficacy, limiting treatment outcomes. To address this issue, MSNs have emerged as a promising drug delivery platform. MSNs can enable targeted drug delivery, thereby increasing drug accumulation at the intended site of action while minimizing adverse effects on healthy tissue. This targeted approach has the potential to enhance therapeutic efficacy and reduce side effects.¹³⁶ Dyslipidemia drugs typically function by reducing LDL-C and TG while elevating HDL levels. Although heparin is primarily classified as an anticoagulant, studies have shown its potential in decreasing LDL-C levels. A study by Jin et al in 2024 demonstrated that in vitro tests, including the injection of heparin (HP)/MSN into mice plasma, resulted in a considerable enhancement (p < 0.05) of LDL-C adsorption relative to the control group.¹⁵³ Several mechanisms were proposed to explain the LDL-C-lowering effect of HP/MSN. First, HP/MSN served as a solid-phase extraction medium that directly adsorbed LDL-C, which reduced the plasma concentration of LDL-C. LDL-C bound to HP/MSN could subsequently be released using a high-concentration sodium chloride solution, confirming that HP/MSN adsorbs LDL-C via physical sequestration. Second, the development of HP/MSN-LDL-C complexes disrupted the usual interaction between blood lipids and lipase, leading to diminished lipase activity. This work employs PMS, a kind of mesoporous silica, as the control, which possesses the capacity to adsorb LDL-C directly. The PMS was subsequently amalgamated with heparin, resulting in the HP/MSN test chemical. The profile test results obtained using TEM show irregular shapes, suggesting that both PMS and HP/MSN can substantially adsorb LDL-C. Nevertheless, the capacity of HP/MSN to bind LDL-C is significantly greater than that of PMS alone. Furthermore, HP/MSN exhibits a reduced capacity for HDL adsorption in comparison to MSN, suggesting its potential for greater efficacy. These findings suggest a mechanistic basis for potential LDL-C reduction in vivo, which could contribute to plaque stabilization.

Conversely, statins represent a category of antidyslipidemic drugs extensively utilized in treatment. Senescent foamy macrophages are prevalent and exert harmful effects across all stages of atherosclerosis, as evidenced by a comprehensive transmission electron microscopy analysis of atherosclerotic plaques. The removal of these cells has been associated with lesion regression. It has been suggested that the senescent cells present in both early and mature atherosclerotic plaques may correspond to pro-inflammatory macrophages, and their elimination could suppress plaque development and enhance plaque stability. Modified LDL, including oxLDL, can trigger the accumulation of monocytes and macrophages in the subendothelial region during inflammatory atherosclerosis, facilitating their differentiation into foam cells, which contributes to the formation of detrimental atherosclerotic plaque. A 2021 in vitro study by Pham et al demonstrated that rosuvastatin encapsulated in MSN resulted in significantly (p < 0.01) lower LDL oxidation (2.8%), in contrast to free rosuvastatin (10%), indicating a potential role in mitigating plaque development.³

In addition to antidyslipidemic agents, researchers also studied antihypertensive drugs. Antihypertensives are crucial in mitigating the onset of atherosclerosis. In the research performed by Farooq et al¹⁴⁹ on MSNs loaded with sodium nitroprusside (SNP), a potent vasodilator used in hypertension treatment. SNP relaxes vascular smooth muscle, resulting in the dilation of peripheral arteries and veins. MSNs and fluorescein isothiocyanate (FITC) MSNs were introduced into the organ-bath system at a concentration of 1.96 × eqn. The observed trend in the vasodilation of aortic arteries incubated with MSNs containing SNP resulted in a notable decrease in constriction. The MSNs containing SNP exhibited a rapid release of SNP within the initial 20 minutes, yielding a 57.74% relaxation relative to the SNP control. The maximum relaxation was 77.08%, achieved at 125 minutes. The result suggests that MNPs-SNP may be more efficacious than employing only SNP. These results highlight the potential of MSN formulations in improving vascular responsiveness and reducing blood pressure, key therapeutic targets in atherosclerosis prevention.

Bharati et al¹⁴² further investigated Efonidipine hydrochloride ethanolate (EFE) in 2024 using the non-everted sac technique to assess its permeation across three specific rat intestinal segments: the duodenum, jejunum, and ileum. The study compared the permeability of pure EFE and EFE with Solid Dispersion (EFESD). Results indicated that EFESD exhibited approximately a twofold enhancement in the permeability coefficient and permeation rate relative to EFE, as observed in the KRS (pH 7.4) and isopropyl alcohol (70:30 v/v) mixture. This contributed to enhancement in EFE’s solubility and favorable distribution across the intestinal barrier. The non-specific absorption of EFE via the small intestine was evidenced by the absence of notable differences in penetration across the three intestinal regions.

While these in vitro results suggest promising physicochemical and pharmacological enhancements, direct correlations with clinical outcomes—such as plaque regression or blood pressure normalization—remain limited. Future research should prioritize the integration of pharmacodynamic data to substantiate the translational relevance of these findings.

In vivo Studies

An in vivo study by Bharati et al¹⁴² in 2024 using Wistar rats with acute renal hypertension demonstrated the enhanced antihypertensive efficacy of mesoporous silica-based amorphous formulations of the BCS class II drug EFE. The EFE-loaded mesoporous silica enhances solubilization in the gastrointestinal tract (GIT), increasing its concentration at the absorption site and resulting in better antihypertensive efficacy. Notably, the EFE-loaded mesoporous silica achieved a rapid reduction in mean arterial blood pressure (MABP) to 73.33 ± 2.22 mmHg, compared to 83.82 ± 3.13 mmHg with pure EFE, indicating statistically significant improvement (p < 0.0001). This suggests greater potential for clinical blood pressure control and atherosclerosis prevention.

Concurrently, Jadhav and Vavia developed a dodecylamine template-based MSN carrier to enhance the delivery of poorly soluble fenofibrate by improving drug loading and in vivo efficacy.¹⁹ The formulation was evaluated using a two-phase Triton-induced hyperlipidemia model in male Wistar rats. In Phase I, the MSN-based formulation significantly reduced both cholesterol (46.4 ± 5.8 mg/dL, p < 0.001) and triglyceride (78.88 ± 10.6 mg/dL, p < 0.001) levels at 24 hours post-administration, compared to the plain drug, which only reduced cholesterol to 197.70 ± 20.6 mg/dL and triglycerides to 321.67 ± 16.8 mg/dL. Similarly, in Phase II, further reductions were observed at 48 hours, with cholesterol at 50.64 ± 8.4 mg/dL (p < 0.001) and triglycerides at 67.63 ± 7.2 mg/dL (P < 0.001), while the plain drug achieved levels of 80.52 ± 12.2 mg/dL and 111.65 ± 20.1 mg/dL. These results highlight the superior lipid-lowering efficacy of the MSN-based formulation in both phases of the Triton test, which can be attributed to the MSN carrier’s enhancement of fenofibrate dissolution, potentially leading to improved absorption and consequently higher blood concentrations (bioavailability). This pharmacokinetic improvement translates into a meaningful enhancement in therapeutic lipid regulation, which is critical in the management of atherosclerosis.

Additionally, Jin et al proposed a novel method using MSN to create HP-MSN, which allows selective removal of LDL-C from the bloodstream without lowering the HDL-C levels or interfering with total protein in blood.¹⁵³ In vivo studies using Sprague–Dawley rats fed a high-fat diet showed MSN-HP selectively adsorbed LDL-C (6.5 ± 0.73 mM vs 8.6 ± 0.76 mM, p < 0.001) without affecting other plasma components, thereby reducing collagen content subsequent to intravascular plaque formation (3.66% ± 1.06% vs 1.87% ± 0.79%, p < 0.05) on the aortic wall and inhibiting vascular remodeling (27.2% ± 6.55% vs 38.3% ± 1.99%, p < 0.05) compared to the control group treated with phosphate buffered saline (PBS). These findings provide strong evidence that MSN-HP not only modulates plasma lipid levels but also attenuates atherogenesis at the tissue level, an effect driven by electrostatic interaction between the negatively charged surface of MSN-HP and positively charged LDL-C, facilitating selective adsorption, similar to the mechanism observed with MSN.

Yang et al¹³³ developed a novel drug delivery system, breviscapine-loaded MSN prepare using Ultrasound Assisted Solution Enhanced Dispersion by Supercritical Fluids (BRE-MSN USEDS), a natural flavonoid extracted from Erigeron breviscapus (Vant) with known cardiovascular benefits, within mesoporous silica nanoparticles (MSNs). To assess the enhanced pharmacokinetic profile of BRE-MSN USEDS, an in vivo study was conducted. The plasma concentration profile of BRE-MSNs demonstrated a significantly enhanced drug absorption compared to BRE powder. After oral administration, the AUC0–∞ and Cmax for the BRE powder were 3.07 μg/h·mL and 0.46 μg/mL, respectively. The BRE-MSNs showed substantially higher AUC0–∞ and Cmax values than the BRE powder (P<0.05). Specifically, the AUC0–∞ of BRE-MSNs-USEDS was 1.96 times greater, and the Cmax was 2.13 times higher compared to BRE powder. While this study focused on pharmacokinetic improvements, the known cardiovascular activity of BRE supports its potential relevance for clinical outcomes such as improved endothelial function or reduced vascular inflammation.

Collectively, these in vivo studies substantiate the pharmacological advantages of MSN-based formulations, demonstrating statistically significant improvements in blood pressure regulation, lipid profile modulation, and attenuation of atherosclerotic plaque. Despite these promising biological effects, future investigations should incorporate standardized clinical endpoints and long-term outcome evaluations to strengthen the translational validity of these findings.

Discussion

Each drug formulation requires its own criteria according to the type of preparation to be produced. In solid preparations, there are criteria that need to be considered, such as physicochemical properties and solubility. High solubility can increase the bioavailability of a drug in the body due to its efficient absorption and distribution at the site of action. Conversely, low solubility can hinder dissolution, resulting in reduced bioavailability and suboptimal therapeutic effects, which may necessitate higher doses. However, increasing the dosage can lead to drug accumulation in the body and a higher risk of adverse effects. MSNs serve as a solution to enhance the solubility of poorly water-soluble compounds, including antihyperlipidemics and antihypertensives drugs. Both types typically exhibit low solubility, necessitating a modification.

The use of MSN in the statin group can enhance the effectiveness of the drug’s action in the body. The effect can be seen in Figure 6. Statins are categorized under the BCS class II, which means the drugs have poor solubility. The poor solubility can result in a low concentration of the drug in the target, which can lead to the drug’s low bioavailability in the body. This low solubility often leads to insufficient drug concentrations at the target site and reduced bioavailability, requiring higher doses to achieve therapeutic efficacy. However, increasing the dose can increase the risk of side effects. MSNs offer an effective solution due to their unique physicochemical properties. The presence of silanol groups on the MSN surface contributes to improved solubility of hydrophobic drugs like statins. In addition, the large surface area and porous structure of MSNs facilitate enhanced drug loading, accelerated release, and improved interaction with biological membranes. These features collectively contribute to increased dissolution rates, improved absorption, and subsequently higher bioavailability. Furthermore, due to their high absorption in the bloodstream and the attainment of therapeutic dosages, statins/MSN can block the enzyme HMG-CoA reductase, a crucial element in cholesterol synthesis, more effectively compared to pure statins. Inhibiting HMG-CoA reductase prevents HMG-CoA from being converted to mevalonate, which inhibits the synthesis of cholesterol and impacts the clinical profile by lowering the total cholesterol value, thereby resolving the dyslipidemia problem.

Figure 6 Speculated mechanism by which mesoporous silica nanoparticles (MSNs) improve the efficacy of statins.

The pharmacological activity of antihypertensive drugs, such as ARBs, is significantly enhanced when loaded into MSNs compared to the pure drug forms, as shown in Figure 7. This enhancement is attributed to the nanosized particles of MSNs, which increase drug solubility and facilitate a controlled, gradual release of ARBs into the body, improving bioavailability via a diffusion-driven mechanism. The passive diffusion process enables ARBs to dissolve more effectively in the body’s aqueous compartments, such as the interstitial spaces, by maintaining a concentration gradient. This gradient drives ARBs from regions of higher to lower concentration until equilibrium is achieved. Furthermore, the incorporation of ARBs into MSNs allows them to traverse water-filled pores in the endothelial lining of blood vessels. The distribution of ARB molecules in an individual, single-molecule form within the pores of the MSNs creates a supersaturated solution in the aqueous environment, further enhancing solubility.²³ A supersaturated solution of ARB will increase the amount of molecules of ARB to block the action of angiotensin II by inhibiting its binding to the angiotensin II type 1 (AT1) receptor compared to pure ARBs, leading to significant enhancement of the efficacy of ARBs.¹⁵⁷ ARBs loaded into MSNs exhibit more competitive binding to the angiotensin II receptor (AT1) that inhibits the attachment of angiotensin II compared to pure ARB. This inhibition prevents oxidative damage to endothelial cells, thereby preventing endothelial dysfunction, which is a primary contributor to the pathogenesis of atherosclerosis. Blocking AT1 receptor activation helps widen blood vessels by reducing signals that cause them to narrow, leading to a notable drop in blood pressure.¹⁵⁸

Figure 7 Speculated mechanism of the improvement of angiotensin receptor blockers (ARBs) with mesoporous silica nanoparticles (MSNs).

Despite their therapeutic potential, particularly in enhancing the efficacy of anti-atherosclerosis treatments, the clinical application of MSNs remains significantly limited. Most MSN-related studies are still confined to preclinical investigations, including in vitro and small-animal in vivo models. Only a few MSN-based formulations have advanced to early-phase clinical trials, and comprehensive data on their long-term safety, biodistribution, metabolism, and pharmacodynamic behavior in humans are lacking. These gaps reduce regulatory confidence and hinder the approval of MSNs as viable drug delivery systems.

Additionally, the large-scale industrial production of MSNs faces considerable challenges. Conventional batch-based sol-gel synthesis methods are difficult to scale due to their multistep procedures, high material and energy demands, and inconsistencies in particle size uniformity and surface characteristics. In response, microfluidic-based synthesis has attracted growing attention for its potential to enable continuous, scalable, and reproducible MSN production with precise control over size, morphology, and drug-loading efficiency. The adoption of such advanced manufacturing technologies could help bridge the gap between laboratory-scale research and industrial pharmaceutical production.

Moreover, recent studies have shown that MSN synthesis methods—such as sol-gel and surfactant-templating—can significantly influence particle uniformity, surface characteristics, and drug loading capacity. However, the lack of standardized, head-to-head comparisons conducted under consistent conditions continues to hinder the optimization of MSN design for therapeutic applications. In parallel, the safety profiles of MSNs, including long-term toxicity, immunogenicity, and clearance pathways, remain insufficiently characterized. While emerging research has begun to address these concerns, more comprehensive and systematic evaluations are essential to determine the clinical feasibility of MSN-based formulations, particularly for long-term therapeutic use.

Compared to other well-established nanocarriers—such as liposomes, dendrimers, and polymeric nanoparticles—MSNs offer several unique advantages, including high surface area, tunable pore size, and exceptional physicochemical stability. These features enable efficient drug loading, protection of labile compounds, and controlled drug release. In addition, MSNs can be readily surface-functionalized to achieve targeted drug delivery without compromising their structural integrity. However, unless the clinical and industrial limitations are systematically addressed, the broader translation of MSNs into real-world therapeutic applications will remain restricted.

While this review highlights promising outcomes regarding the use of MSNs, it is important to acknowledge the methodological limitations of the cited studies. Although many investigations have utilized in vivo models, relatively few have conducted integrated in vitro and in vivo assessments within the same study. This lack of comprehensive, multi-tiered evaluation limits the understanding of mechanistic correlations and weakens the interpretation of translational relevance. Additionally, inconsistencies in experimental design, dosing strategies, and outcome measures across studies further complicate efforts to draw consistent and generalizable conclusions regarding the clinical potential of MSN-based drug delivery systems. These challenges underscore the need for more standardized, methodologically rigorous, and cohesively designed research moving forward.

Conclusions

In conclusion, MSNs have demonstrated significant potential in enhancing the solubility, bioavailability, and pharmacological efficacy of antihyperlipidemic and antihypertensive drugs, as supported by both in vitro and in vivo studies. Unlike conventional enhancement methods that are hindered by issues such as aggregation and polymorphism, MSNs offer unique physicochemical advantages, such as tunable pore size, high surface area, and modifiable surface chemistry, that enable efficient drug loading, stabilization, and targeted delivery. However, the clinical translation of MSN-based formulations remains limited by concerns related to long-term toxicity, immunogenicity, clearance pathways, and challenges in large-scale manufacturing. These difficulties are further compounded by regulatory uncertainties due to the absence of standardized evaluation frameworks for nanoparticle-based systems. Future research should prioritize comprehensive safety profiling, the development of scalable synthesis methods, and well-designed clinical trials to support the safe and effective integration of MSNs into therapeutic practice, particularly in the treatment of atherosclerosis.

Author’s Perspective

In the Asia-Pacific region, the prevalence of hypertension ranges between 10.6% and 48.3%, and elevated low-density lipoprotein (LDL) levels range between 7.8% and 47.2%, highlighting the urgent need for pharmacists to develop innovative therapeutic strategies. Mesoporous silica nanoparticles (MSNs) have been acknowledged as a promising strategy for next-generation pharmaceutical carriers due to their remarkable capacity to enhance the therapeutic efficacy of antihyperlipidemics and antihypertensives. Compared to conventional physical and chemical methods currently employed to address low solubility issues in antihyperlipidemic and antihypertensive drugs, these existing approaches primarily improve solubility, dissolution rate, and physicochemical properties without significantly reducing the required dose, potentially leading to drug toxicity. Furthermore, traditional methods often fail to prevent uncontrolled polymorphism, which poses a risk of clinical failure due to undesirable solid-state conversion. Besides only enhancing solubility and dissolution profiles, MSNs also promote uniform drug distribution by enabling targeted drug delivery. This approach significantly increases drug concentration at the intended site of action while minimizing adverse effects on surrounding healthy tissues, thereby improving therapeutic efficacy and potentially reducing side effects.

This review presents a comprehensive overview of previous studies on antihypertensive and antihyperlipidemic drugs loaded into MSNs, emphasizing their effects on dissolution and pharmacological activity based on both in vitro and in vivo studies. The types of MSNs developed by various researchers, including SBA-15, SLH, CD9-HMS N@RSV, KIT-6, MCM-41, MCF-26, and HMC, are briefly summarized. Furthermore, this review discusses the key attributes of MSNs that contribute to the enhancement of solubility, dissolution rate, and bioavailability, which consequently improve pharmacological efficacy. This review also presents the underlying mechanisms by which MSN-based drug delivery systems enhance the bioavailability of antihyperlipidemic and antihypertensive drugs. This review is expected to provide valuable insights into the potential of MSNs as innovative carriers in cholesterol and hypertension therapies.

Despite significant advancements in the development of MSNs as advanced drug delivery systems for hypertension and hyperlipidemia, several challenges hinder their translation into commercially available therapeutic regimens. One of the primary obstacles is the limited progression of MSNs into clinical trials, as most studies are confined to preclinical in vitro and in vivo studies. The absence of comprehensive clinical investigations regarding their long-term safety, pharmacokinetics, and pharmacodynamic profiles poses a critical barrier to regulatory approval. Secondly, the large-scale industrial production of MSNs becomes challenging due to the complexity of synthesis protocols, which often involve multiple steps, high-cost materials, and stringent physicochemical control to ensure uniform particle size, pore structure, and drug loading efficiency. Developing simple, cost-effective, and reproducible fabrication methods is essential to facilitate and develop MSN industrialization as well as meet the demands of large-scale pharmaceutical manufacturing. Addressing these challenges through interdisciplinary collaboration and technological advancements is crucial to unlocking the full potential of MSNs as commercially viable platforms for antihyperlipidemic and antihypertensive therapies.

Acknowledgments

We would like to thank Universitas Padjadjaran for APC.

Funding

This research was funded by the National Research and Innovation Agency (BRIN, RIIM2) and the Indonesia Endowment Funds for Education (LPDP) to Diah Lia Aulifa (No.: 61/IV/KS/5/2023; No.: 2131/UN6.3.1/PT.00/2023).

Disclosure

The authors declare no conflicts of interest for this review article.

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