Introduction
As one of the essential trace elements for the human body, selenium plays a crucial role in living organisms. Since selenium cannot be synthesized in animals, obtaining it from the external environment is the only way.1 Selenium in nature usually exists in two forms: organic selenium and inorganic selenium. They differ significantly in chemical structure, absorption mechanism, and safety.
Inorganic selenium includes sodium selenite and sodium selenate, which exist in the form of inorganic salts. They need to be methylated by the liver before being utilized, have a low biological utilization rate, a narrow toxicity threshold, and are prone to causing poisoning when overconsumed.2 Organic selenium includes selenomethionine, selenocysteine, and selenium-enriched yeast, which are compounds formed by the combination of selenium and carbon. They can be absorbed through active transport via amino acid channels and have a long retention time in the body.2
Over the past few decades, the emergence of nanomedicine has changed people’s perspectives on drug development. As an emerging science, nanomedicine provides new ideas and methods for the treatment of many diseases. Nanoparticles prepared using nanotechnology have characteristics that are different from traditional materials, such as ultra-small particle size, large surface area, and unique morphological features (Figure 1).
To date, metal nanoparticles such as Ag, Au, Ce, Fe, Se, Si, Ti, and Zn hold a special position in the field of nanotechnology. They not only have unique biological functions but also have great potential as carriers for chemotherapy drugs, proteins, and siRNA.3 Among these nanoparticles, selenium nanoparticles (SeNPs) hold the most important position. Compared with other metallic nanoparticles, SeNPs possess distinct advantages as self-therapeutic agents.
For instance, while gold nanoparticles (AuNPs) have demonstrated efficacy in reducing neurodegeneration in Huntington’s disease models and alleviating acute lung inflammation via inhalable spike-conjugated formulations, they primarily function as drug carriers or photothermal agents.4,5 In contrast, SeNPs are metabolized into active selenoproteins (GSH-Px), enabling sustained intrinsic antioxidant activity. Compared with traditional selenium compounds, SeNPs have unique physical and chemical properties. They can not only exert the functions of inorganic selenium and organic selenium, but also have high bioavailability and low toxicity (Figure 2).
For instance, the acute oral LD50 of Sargassum fusiforme polysaccharide-modified SeNPs was 88.76 mg Se/kg, while the 28-day repeated-dose no-observed-adverse-effect level (NOAEL) of Na2SeO3 was 4.43 mg Se/kg. This indicated that SeNPs effectively reduced the acute toxicity of selenium.6 This improved safety profile, combined with their ability to simultaneously modulate multiple pathogenic pathways, positions SeNPs as particularly suitable candidates for chronic cardiometabolic diseases. They have received widespread attention in the fields of analysis and detection, food, agriculture, and biomedicine.Figure 1Representative nanoparticles for drug delivery.
Representative nanoparticles include mesoporous nanoparticle, liposome, dendrimer, solid lipid carrier, hydrogel, micelle, polymeric nanoparticle, carbon nanotube, nanogel, nanocage, quantum dot, amphiphilic cyclodextrin, and viral carrier. Figure generated with BioRender.com.Diagram of 13 labeled nanoparticle types for drug delivery in a three-row grid.A grid of 13 stylized nanoparticle icons, each with a printed label beneath it, arranged in three rows. Top row labels, left to right: Mesoporous nanoparticle, Liposome, Dendrimer, Solid Lipid Carrier, Polymer micelle.
Middle row labels, left to right: Hydrogel, Micelle, Polymeric Nanoparticle, Carbon Nanotube. Bottom row labels, left to right: Nanogel, Nanocage, Quantum Dot, Amphiphilic Cyclodextrin, Viral Carrier. The icons include a porous sphere, a layered vesicle with internal shapes, a branching tree-like structure, a ring of repeated units, a central core with radiating chains, a smooth sphere, a circular assembly with inward chains, a tangled polymer-like ball, a cylindrical tube with a lattice pattern, a networked gel sphere with protruding chains, a cage-like polyhedral outline, a concentric multi-ring particle, a thick-walled ring and a circular carrier containing a squiggled strand.Figure 2The toxicity profile of selenium species.
This figure compares the relationship between various selenium particle sizes and biological safety. Figure generated with BioRender.com.A size scale comparing inorganic selenium to modified selenium nanoparticles across nanometer ranges.
Atherosclerosis (AS) is an ischemic lesion characterized by the accumulation of lipids in the inner lining of arterial walls, eventually leading to narrowing or complete blockage of the vessel lumen.7 Research indicates that AS is divided into four stages: the fatty streak stage, the fibrous plaque stage, the atheromatous plaque stage, and the subsequent lesion stage of the plaque. Many factors (smoking, drinking, hyperlipidemia, obesity) can promote the occurrence of AS. To date, treatment strategies for AS mainly include drug therapy, surgical interventions, and lifestyle modifications.8 Among these strategies, the effect of drug therapy is not significant.
Surgical interventions have the risks of postoperative thrombosis and vascular restenosis.9 Lifestyle modification can only be used as a preventive and adjunctive treatment.
Non-alcoholic fatty liver disease (NAFLD) refers to a clinical pathological syndrome characterized mainly by excessive fat deposition in liver cells, excluding alcohol and other definite liver-damaging factors. The stages of NAFLD include non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis.10 In blood biochemical tests, NAFLD is typically characterized by elevated levels of TG, AST, and ALT. Liver biopsy is regarded as the gold standard for diagnosing NAFLD, but it is an invasive method with serious limitations and is not applicable to all patients.
Traditional ultrasound examinations rely heavily on the operator’s experience and are highly subjective, which may lead to missed diagnoses. CT scans can detect lipid accumulation in liver cells but cannot determine the stage of liver fibrosis. Serum marker diagnosis suffers from low accuracy and sensitivity.
Currently, NAFLD treatment primarily involves lifestyle interventions (low-calorie diet, exercise, weight loss).11
For the two common chronic diseases, NAFLD and AS, exploring and developing related drugs holds great potential. This article not only introduces and summarizes the pharmacological effects, applications, synthesis, stabilizers, and characterization of SeNPs, but also focuses on summarizing and analyzing the pathogenesis of AS and NAFLD, the core function of SeNPs in improving NAFLD and AS, and the research progress of SeNPs in NAFLD and AS.
Epidemiological data indicate that the global prevalence of NAFLD has reached approximately 38%, with projections suggesting 41.4% by 2050, affecting an estimated 122 million US adults.12 Notably, there is a consistent and independent association between cardiovascular disease and NAFLD. Compared to individuals without hepatic steatosis, those with NAFLD exhibit a 39% increased hazard for cardiovascular disease events.13 AS and NAFLD are increasingly recognized as interrelated manifestations of systemic metabolic dysfunction, often coexisting in patients with obesity, insulin resistance, and dyslipidemia. The shared pathophysiological basis of these diseases (oxidative stress, chronic inflammation, immune dysregulation, lipid metabolism disorders) provides a compelling rationale for developing therapeutics that can simultaneously target both conditions.
In this context, SeNPs offer distinct advantages over conventional selenium compounds and other nanoplatforms. Unlike inorganic or organic selenium, SeNPs exhibit enhanced bioavailability, sustained antioxidant activity, and the capacity to modulate multiple signaling pathways (NRF2, NF-κB, PI3K/AKT/mTOR) involved in both AS and NAFLD pathogenesis. Furthermore, SeNPs can be functionalized with targeting ligands to achieve site-specific delivery to atherosclerotic plaques or hepatic tissue, thereby maximizing therapeutic efficacy.
Currently approved therapies for AS include statins, antiplatelet drugs, and antihypertensive drugs. Furthermore, no drugs targeting NAFLD (steatosis stage) have been approved for treatment. SeNPs can serve as a supplement to existing treatment methods, potentially reducing the need for polypharmacy and mitigating the side effects associated with long-term use of conventional medications.
In summary, compared with previous reviews on SeNPs, the novelty of this review lies in filling the following key knowledge gaps: integrating the shared pathological mechanisms of AS and NAFLD, critically evaluating the efficacy differences among different SeNPs, raising doubts about the safety of long-term administration, summarizing the progress and advantages of targeted delivery systems, clarifying the obstacles to translation and proposing future research directions.
Synthesis, Stabilizers, and Characterization of SeNPs
The biological utilization rate and activity of SeNPs are affected by their morphology and particle size. Different synthesis methods and conditions directly influence the morphology and particle size of SeNPs (Table 1 and Table 2). Based on the synthesis conditions and principles, the synthesis methods of SeNPs can be classified into three methods: chemical synthesis method, physical synthesis method, and biological synthesis method (Figure 3).
Physical synthesis methods of SeNPs mainly include the deposition method and the laser ablation method. The advantages of physical synthesis methods include low pollution and fast preparation speed, while the disadvantages include high equipment cost and poor stability. The deposition method is the most popular physical method for synthesizing SeNPs.
Laser beams with wavelengths of 248 nm and 532 nm have been used to synthesize SeNPs. These nanoparticles were deposited onto various surfaces, including glass slides, gold-coated metal films, and silicon wafers.14 The laser ablation method utilizes high-energy laser beams to bombard the selenium source, thereby reducing the high-valent selenium to elemental selenium. The chemical reduction method is a commonly used chemical synthesis method for preparing SeNPs.
This method uses inorganic selenium as the selenium source and reduces it to elemental selenium using a reducing agent. SeNPs prepared by the chemical reduction method are usually spherical and carry a negative charge. When synthesizing SeNPs in an ionic solution, stabilizers need to be added to maintain the stability of the nanoparticles.
Additionally, when using chemical reagents, some dangerous by-products are often produced, and the SeNPs synthesized by chemical synthesis are susceptible to acid, alkali, solvents, and heat, resulting in aggregation or precipitation.15 Biological synthesis of SeNPs mainly utilizes the reduction effect of bacteria, fungi, or green plants to convert the highly toxic inorganic selenium into less toxic Se0.16 Compared to physical and chemical synthesis, biological synthesis is safer, with convenient raw material sources and low cost. Moreover, the SeNPs synthesized by biological synthesis do not aggregate and do not require the addition of stabilizers. Notably, bare SeNPs are unstable in aqueous solutions and are prone to aggregation and precipitation, resulting in a significant reduction in their efficacy.
Therefore, adding stabilizers during the preparation of SeNPs can effectively disperse SeNPs.17 Research indicates that the stabilizers for SeNPs are generally biological macromolecules, such as polysaccharides, proteins, and polyphenols. Proteins, as large macromolecular substances with diverse structures, have many modification groups and have always been high-quality stabilizers. Research indicates that proteins mainly adhere to the surface of the selenium core through three non-covalent forces: hydrophobic interactions, electrostatic interactions, and hydrogen bonds, thereby maintaining the colloidal stability of SeNPs.18 Polysaccharides are basic substances of living organisms and can be found everywhere in nature.
Due to the presence of numerous active functional groups in polysaccharides, they are easily modified and can combine with other substances to form complexes such as glycoproteins and glycolipids. At the same time, the special branching structure and large number of active groups in polysaccharides can modify the surface of SeNPs, possessing the potential to be developed into nanocarriers for drug delivery.19 Notably, most of the current reports on polysaccharide-SeNPs focus on individual polysaccharide-SeNPs, lacking comparisons among different polysaccharide-SeNPs. Different polysaccharides have different properties, and thus their modification effects on SeNPs and biological activities also vary.
Polyphenolic substances and SeNPs both have strong antioxidant activity.20 When using polyphenolic substances as stabilizers, attention should be paid to the environmental pH value, as pH is a key factor affecting their colloidal stability, particle size distribution, and biological activity. A lower pH value will protonate the phenolic hydroxyl groups in polyphenolic substances, reducing their electrophilic ability and leading to a decrease in their antioxidant capacity, causing SeNPs to easily aggregate. In neutral or alkaline environments, the phenolic hydroxyl groups in polyphenolic substances remain in an anionic state, enhancing their electron-donating ability and improving the antioxidant capacity of polyphenolic substances.
Therefore, the prepared SeNPs can maintain good dispersibility. Table 1Comparison of Synthesis Methods and Physicochemical Properties of Representative SeNPsSynthesis MethodReducing AgentSize (nm)Zeta Potential (mV)MorphologyPolydispersity IndexRef.Chemical reductionAscorbic acid/Polyvinyl alcohol20-120 (Dry diameter)137–172 (Hydrodynamic diameter)−7.79 to −19.6Spherical0.049–0.306[21]Chemical reductionAscorbic acid/Grape seed extract74.86 ± 6.07−30.42 ± 0.54Spherical0.159 ± 0.028[22]Biological (bacteria)B. subtilis BSN313530−26.9Spherical/[23]Biological (fungi)Y. lipolytica110−34.51 ± 2.41Spherical/[24]Biological (plant)Quercetin48.85−20.3Spherical0.245[25]Physical (laser ablation)/5–25/Spherical/[26]Table 2Effects of Different Stabilizers on SeNPsStabilizer ClassExampleStabilization MechanismSize (nm)Zeta Potential (mV)Ref.ProteinBSAHydrophobic/electrostatic interactions, Hydrogen bond38.5Negative[27]PolysaccharideCSElectrostatic interactions, Steric hindrance65.8Positive[27]PolysaccharideLCSMucin-associated microbiota modulation//[28]PolyphenolEpigallocatechin gallateπ–π stacking, H-bonds, Phenolic coordination89.3−30.6[29]OligonucleotideA151 + LacNAcGalectin-388.90 ± 1.45−21.1 ± 1.5[30]Figure 3Classification of SeNPs synthesis strategies. The representative synthesis methods of SeNPs include physical synthesis method (deposition method, laser ablation method), chemical synthesis method (chemical reduction method), and biological synthesis method (bacteria, fungi, green plants).
Figure generated with BioRender.com.A three part diagram classifying SeNPs synthesis into physical, chemical and biological methods.
Characterization of SeNPs is necessary after synthesis. The characterization of SeNPs should focus on size, morphological structure, crystallinity, and stability. Common verification methods include TEM, SEM, DLS, XRD, HRTEM, FTIR, XPS, EDX, UV-Vis, and TGA.31,32 A critical comparison of various SeNPs reveals that the choice of stabilizer and synthesis method profoundly influences physicochemical properties and biological outcomes.
Notably, most comparative studies are limited to only two formulations. Therefore, it is of great importance to conduct a systematic comparison of multiple stabilizers (proteins, polysaccharides, polyphenols, and synthetic polymers) under standardized conditions in the future.
Pharmacological Effects of SeNPs
Microbial infections are a significant factor contributing to global morbidity and mortality rates. Current research indicates that SeNPs have strong antibacterial activity. SeNPs can effectively inhibit common infectious bacteria, such as Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa.
Additionally, SeNPs also show good preventive and therapeutic effects on multi-drug resistant bacteria like Klebsiella pneumoniae.33 It is worth noting that the antibacterial activity of SeNPs varies in different studies. This variation is mainly related to the particle characteristics and synthesis methods of SeNPs.34 The antibacterial mechanism of SeNPs includes inducing bacteria to produce a large amount of reactive oxygen species (ROS), destroying the integrity of the bacterial cell membrane, and damaging the DNA structure.35 In addition to antibacterial properties, SeNPs also exhibit significant antiviral activity against various viruses. In hepatitis B virus-infected hepatocytes, SeNPs reduce pro-inflammatory cytokines and alleviate DNA damage.36 For EV71, the complex of SeNPs and siRNA can effectively inhibit viral replication.
Moreover, CS-SeNPs can inhibit PRRSV, exerting their effect by reducing oxidative stress and apoptosis.36 SeNPs can also inhibit H1N1 influenza virus infection, reducing the generation of ROS and cell apoptosis. These studies demonstrate that SeNPs can not only enter cells to inhibit viral replication, but also inactivate viruses through surface contact, presenting a broad-spectrum antiviral application prospect.
Diabetes has become a global public health challenge, with the number of patients continuously increasing and showing a trend toward younger age. Therefore, exploring new treatment methods holds significant importance for the prevention and treatment of diabetes. In streptozotocin-induced diabetic rats, SeNPs reduced glucose-6-phosphatase activity, boosted glucose-6-phosphate dehydrogenase activity and glycogen stores.37 In the same animal model, SeNPs alleviated the oxidative stress caused by diabetes, particularly in testicular tissue.38 Interestingly, SeNPs also alleviated diabetic nephropathy during pregnancy in diabetic female rats.39 Some studies have indicated that SeNPs can promote insulin production and cell proliferation.
In conclusion, SeNPs are expected to become a nanomaterial for the treatment of diabetes.40,41
Cancer is a disease with the highest mortality rate in the world, seriously threatening human life and health. To date, the treatment method for cancer is usually chemotherapy. However, most chemotherapy drugs are hydrophobic and have poor selectivity.
While killing tumor cells, they are prone to damaging normal tissues, thereby causing adverse reactions and toxic side effects in the human body. Therefore, new drug design and targeted drug delivery have gradually become hot topics in cancer research. In recent years, more and more nanomaterials have been applied in the treatment of cancer.
The evidence suggests that SeNPs have significant inhibitory effects on various malignant tumors such as liver cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, and prostate cancer.41 Their anticancer mechanisms mainly include inhibiting cell proliferation, promoting cell apoptosis, inhibiting tumor angiogenesis, and regulating immune responses.42 SeNPs have high selectivity for normal cells and cancer cells, and can preferentially accumulate in cancer cells to exert anticancer effects. In addition, SeNPs can be used as carriers for anticancer drugs, overcoming their hydrophobicity and delivering them to cancer cells for synergistic effects.43
Neurological diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and dementia mainly affect the elderly population. There are numerous difficulties in drug delivery to the brain, especially due to the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB), which restrict the entry of therapeutic molecules.44 Therefore, exploring new intervention methods is of great significance. Compared with traditional treatment methods, SeNPs have demonstrated significant efficacy in treating these neurological disorders.
Functionalized SeNPs have shown the ability to cross the BBB. A large number of studies have shown that SeNPs exert neuroprotective effects through the following mechanisms: (1) SeNPs downregulate pro-inflammatory cytokines, regulate neuroinflammation, and thereby create a microenvironment conducive to neuroprotection. (2) SeNPs inhibit oxidative stress and inflammation, thereby blocking the response that stimulates tau kinases and reducing excessive phosphorylation of tau protein.
(3) SeNPs regulate the balance between kinases and phosphates, stabilize microtubule structure, and prevent tau protein from aggregating to form toxic fibers. (4) SeNPs remove excessive ROS, maintain ATP production and calcium ion homeostasis, protect mitochondrial function, and reduce the release of pro-apoptotic factors, thereby protecting neurons from energy depletion and cell death.14
In addition to the aforementioned protective effects, SeNPs also play a role in improving conditions such as inflammatory bowel disease, ulcerative colitis, psoriasis, asthma, Crohn’s disease, osteoarthritis, AS, and NAFLD45,46 (Figure 4). From the perspectives of AS and NAFLD, these pharmacological effects of SeNPs are also closely related to both conditions. Firstly, in the progression of AS and NAFLD, SeNPs can indirectly alleviate vascular endothelial and liver damage by inhibiting the excessive proliferation of pathogenic bacteria and reducing the production and entry of LPS into the bloodstream.
Secondly, diabetes is widely regarded as an important factor promoting the occurrence and progression of AS and NAFLD. By improving insulin resistance and hyperglycemic conditions, SeNPs can improve glycolipid metabolism disorders and reduce the degree of inflammation in the vascular wall and liver. Thirdly, some of the cell signaling pathways (PI3K/AKT/mTOR pathway) regulated by SeNPs during the anticancer process also play an important role in the progression of AS and NAFLD.
By inhibiting these pathways, SeNPs may help to simultaneously slow down the progression of AS plaques and the abnormal accumulation of liver fat. Fourthly, the significant efficacy of SeNPs in inflammatory bowel disease, psoriasis, osteoarthritis and other inflammatory-related diseases further strengthens SeNPs’ position as a systemic inflammatory regulator. Although these diseases have different organ targets, they all share the core pathological feature of excessive activation of oxidative stress and inflammatory signaling pathways.
Since the progression of AS and NAFLD depends on these common inflammatory pathways, this provides the possibility for the treatment of both AS and NAFLD.Figure 4Therapeutic spectrum of SeNPs in human diseases. SeNPs significantly improved the progression of atherosclerosis, non-alcoholic fatty liver disease, diabetes, neurological disease, bowel disease, cancer, osteoarthritis, and microbial infection. Figure generated with BioRender.com.Diagram showing SeNPs' therapeutic effects on various human diseases.
The Applications of SeNPs
At present, a large number of studies have shown that SeNPs play an important role in the fields of animal husbandry, agriculture, biomedical materials, and food packaging and storage (Figure 5).Figure 5Multidisciplinary applications of SeNPs. SeNPs are mainly applied in agriculture, animal husbandry, food industry, and biomedical materials. Figure generated with BioRender.com.A circular diagram of SeNPs applications across agriculture, animal husbandry, food and material.
In terms of animal husbandry, SeNPs have improved the reproductive performance of livestock, enhanced their immunity, and boosted their production performance and quality. Selenium is one of the essential trace elements for maintaining male animal fertility. Selenium deficiency may reduce the activity of enzymes related to reproduction, cause an imbalance in the secretion of reproductive hormones, and cause variations in the tissue structure of reproductive organs.
This seriously affects the normal function of mitochondria, the occurrence and maturation of reproductive cells, and thus leads to a decrease in the reproductive performance of animals. Supplementing selenium not only promotes hormone secretion, the development of male animal reproductive organs, and the formation and development of sperm, but also protects sperm cells from damage and improves sperm vitality.47 Selenium is also an essential trace element for the growth, health, and various physiological functions of poultry, and plays a crucial role in the body’s metabolism. The duodenum is the main site of selenium absorption.
It is worth noting that the absorption mechanisms of different forms of selenium sources in livestock and poultry differ.48 SeNPs have smaller particle sizes and specific surface charges, which are conducive to increasing their contact area with the intestinal wall and prolonging the contact time, thereby improving their absorption efficiency. In addition, SeNPs can increase the levels of IgG, IgM, and IgA in the animal body, which can significantly enhance immunity and effectively reduce the probability of disease occurrence.49 Adding SeNPs to feed can improve intestinal mucosal morphology, reduce the proportion of harmful bacteria in the intestine, enhance digestive absorption capacity and feed conversion rate, promote growth and development, and improve meat and egg quality.50
As one of the essential trace elements for plants, an appropriate amount of selenium can enhance the antioxidant capacity and photosynthetic efficiency of crops, thereby promoting their growth and improving their quality. However, long-term exposure to excessive selenium will have the opposite effect and also accelerate the accumulation of heavy metals. In terms of agriculture, SeNPs stimulate the release of soil organic matter and humic acids, thereby improving soil.51 Additionally, traditional pesticides have high toxicity, low insecticidal and fungicidal efficacy, and most of them remain on crops.
Some pesticides even have high permeability and enter the groundwater system, causing environmental pollution. SeNPs have antibacterial and antioxidant effects and can enhance plants’ tolerance to harsh environments.49 In conclusion, the development of new SeNPs fertilizers is a research direction that future agriculture can focus on.
Good food packaging is essential for the storage and transportation of food. Food packaging materials with strong insulation and excellent antibacterial properties are a focus of research. The application of SeNPs in the field of food packaging mainly focuses on the development of active packaging materials with antibacterial and antioxidant properties.52 Additionally, nutritional supplements and functional foods using SeNPs as raw materials have also been developed.52
In terms of biomedical materials, SeNPs are widely used as drug carriers, biosensors, medical filter materials, antibacterial fiber materials, medical dressings and coatings. Beyond conventional SeNPs, the development of targeted delivery systems represents a paradigm shift in improving therapeutic efficacy. However, the translational potential of these targeted systems is limited by manufacturing complexity and cost.
Future designs should prioritize the development of multi-functional nanosystems, while also considering their economic feasibility in clinical applications.
The Pathogenesis of AS and NAFLD
The currently recognized pathogenesis of AS mainly includes lipid deposition, inflammation, oxidative stress, immune imbalance, endothelial damage, and gut microbiota imbalance (Figure 6).Figure 6The common pathogenesis of AS and NAFLD. The common pathogenesis of AS and NAFLD includes oxidative stress, inflammation, immune imbalance, mitochondrial dysfunction, lipid deposition, endoplasmic reticulum stress, insulin resistance, genetic factors, gut microbiota imbalance, and circadian rhythm. Figure generated with BioRender.com.A circular diagram of shared AS and NAFLD mechanisms around liver and artery icons.A circular diagram with a central circle split into two halves, showing a liver icon on the top half and a blood vessel cross section with plaque on the bottom half.
Around the center are labeled circular icons connected by a ring arrow. The labels read, Oxidative stress, Inflammation, Immune imbalance, Mitochondrial dysfunction, Lipid deposition, Endoplasmic reticulum stress, Insulin resistance, Gene, Gut microbiota imbalance and Circadian rhythm.
The pathological basis of AS is lipid deposition. Usually, the initial manifestation of AS is an elevation of TG, TC, and LDL-C levels and a reduction of HDL-C levels. The LDL-C entering the intima is oxidized and modified, becoming “bad cholesterol (ox-LDL)”.
Ox-LDL is more easily phagocytosed by macrophages, forming lipid-filled “foam cells”. These cells accumulate in the vascular wall, forming the core of the early plaque (lipid streak).53
When the production of ROS exceeds the body’s clearance capacity, oxidative stress is triggered. As an important mediator in the formation process of AS, excessive or continuous ROS can directly damage cell membranes and cell nuclei, interact with endogenous vascular active substances in endothelial cells, and oxidize LDL.54 Additionally, superoxide produced by excess ROS can degrade NO, leading to vascular dysfunction. By inhibiting ROS production and increasing the generation of vascular protective factors, the pathological process of AS can be effectively inhibited.55
The inflammatory response is the core factor driving the progression of AS. Monocytes are recruited to the injured site by chemokines, differentiate into macrophages, and release inflammatory factors. The inflammatory response further damages the endothelial structure, promotes more lipid deposition, and activates MMPs to degrade collagen fibers, leading to unstable plaques.56 Additionally, smooth muscle cells in the intima of blood vessels migrate to the intima under the stimulation of inflammatory factors and secrete collagen to form a fibrous cap.
When the fibrous cap of an unstable plaque ruptures, the lipid core is exposed to the blood, triggering platelet aggregation and activation of the coagulation system, resulting in a thrombus. The thrombus may completely block the blood vessel (myocardial infarction), or detach and cause a distal embolism (stroke).57
In addition to lipid metabolism disorders, inflammation, and oxidative stress, immune dysregulation, endothelial damage, and gut microbiota imbalance also play important roles in the progression of AS. There is a close relationship between AS and immune regulation. Many immune cells, such as monocytes, macrophages, dendritic cells, mast cells, T cells, and B cells, affect the progression of AS at all stages.58 The dysregulation or weakening of these immune cells will accelerate the progression of AS.
The role of endothelial cells is mainly to engulf foreign substances, bacteria, and necrotic and aging tissues, thereby maintaining the integrity and permeability of the intima. When endothelial function is impaired, the secretion function of endothelial cells changes, leading to an increase in the expression of chemokines and adhesion factors.59 Gut microbiota imbalance can lead to an increase in harmful intestinal flora and its metabolites, weakening the defense function of the mucosal barrier, accelerating the development of AS plaques or causing plaque rupture.60
Over the past few decades, the “two-hit” theory has been the most classic theory regarding the pathogenesis of NAFLD. This theory posits that the first hit of NAFLD is the deposition of liver lipids and insulin resistance, and the second hit is oxidative stress.61 However, current research indicates that the pathogenesis of NAFLD is extremely complex, involving lipid deposition, oxidative stress, immune dysregulation, inflammation, insulin resistance, and gut microbiota imbalance (Figure 6).
Lipid deposition is the most important mechanism in the early stage of NAFLD progression. De novo lipogenesis (DNL) plays a central role in providing fatty acid sources for liver cells. High-sugar and high-fat diets activate SREBP-1c and ChREBP, upregulate enzymes such as FAS and ACC, and promote DNL.62 At the same time, a large amount of peripheral free fatty acids, dietary fatty acids, and lysosomal-derived fatty acids enter the circulation, leading to lipid peroxidation and lipotoxicity, inducing cell apoptosis and triggering inflammation and fibrosis.63
In terms of immunity and inflammation, NAFLD involves the infiltration of various immune cells.64 During liver injury, dendritic cells and Kupffer cells release a large amount of pro-inflammatory factors and chemokines for response.65 Among them, chemokines promote the further infiltration of inflammatory cells, thereby leading to an intensified inflammatory response, causing cell apoptosis and triggering NASH. To date, inflammatory factors related to NAFLD that have been reported in clinical studies include IL-6, IL-10, IL-1β, IL-17, TNF-α, TGF-β, NF-κB.66 These inflammatory factors can promote the progression of NAFLD by inducing oxidative stress and down-regulating adiponectin.
In terms of oxidative stress, ROS produced by extensive fatty acid metabolism can trigger endoplasmic reticulum stress (ERS). The continuous or excessive activation of ERS activates inflammation and apoptosis through the IRE1, PERK, and ATF6 pathways, accelerating hepatic steatosis. Additionally, mitochondrial dysfunction leads to excessive ROS production.
These ROS attack mtDNA and proteins, activating inflammatory pathways and exacerbating fibrosis.67
Insulin resistance (IR) is a core driving factor in the progression of NAFLD. IR promotes fat breakdown and increases the uptake of free fatty acids by the liver, thereby exacerbating lipid deposition.68 The gut microbiota affects NAFLD through the “gut-liver axis”. Intestinal flora imbalance increases the liver’s absorption of toxins from the intestine, thereby leading to NAFLD.69
In conclusion, we have discovered that the pathological processes of AS and NAFLD constitute a complex network of interactions. Various pathogenic mechanisms play different roles at different stages of AS and NAFLD. By comparing the pathogenesis of AS and NAFLD, we found that both start with lipid deposition and share the common pathway of oxidative stress and inflammatory response.
The core pathological differences between the two mainly include the target organs (vascular wall vs liver) and the main cell types (vascular smooth muscle cells/macrophages vs liver cells/Kupffer cells), but the molecular events driven by them are almost identical. More importantly, there is a clear bidirectional promotion relationship between AS and NAFLD: the excessive secretion of VLDL and inflammatory factors in the liver of NAFLD patients will damage the endothelial function of the blood vessels and accelerate the progression of AS; while the microvascular dysfunction caused by AS will change the hemodynamics of the liver and aggravate the ischemia-reperfusion injury of the liver. This “liver-vascular axis” interaction means that separately intervening in one of the organs is often insufficient to completely block the overall process of the disease.
Therefore, a systematic intervention based on the common pathological basis (oxidative stress, inflammation, immune dysregulation) is the most reasonable strategy. As a nanodelivery agent that can reach the whole body through the bloodstream, SeNPs play a unique role in treating these two diseases due to their multi-target and multi-functional advantages.
The Core Function of SeNPs in Improving NAFLD and AS
Oxidative stress, inflammation, and immune dysregulation are the common pathogenic mechanisms of AS and NAFLD. At the same time, these are also the core pathogenic mechanisms of AS and NAFLD. A large number of studies have shown that SeNPs have antioxidant, anti-inflammatory and immune regulatory functions.
These functions play a core role in improving the progression of AS and NAFLD.
Selenium is the main component of glutathione peroxidase (GSH-Px), and it often participates in the formation of GSH-Px in the form of SeCys. Its main function is to catalyze the reduction reaction of glutathione (GSH) with hydrogen peroxide (H2O2), thereby protecting the integrity of cell membrane structure and function.70 SeNPs have strong antioxidant capacity. This is manifested in the following aspects: (1) SeNPs can directly eliminate free radicals.
(2) After entering the organism, SeNPs can be metabolized into antioxidant selenium enzymes to exert antioxidant effects. (3) After entering the organism, SeNPs can enhance the activity of key enzymes in the body’s antioxidant defense system. (4) SeNPs inhibit protein glycation by binding to protein amino acids and preventing protein structure modification.
Protein glycation is one of the causes of ROS induction in the body.71–73 Mechanistically, SeNPs can regulate multiple signaling pathways such as NRF2, p53, MAPK, JNK, AMPK/mTOR, and increase the expression of genes related to the synthesis of antioxidants.74–77 Notably, compared with other forms of selenium at the same dose, the antioxidant effect of SeNPs is superior. However, current research mainly focuses on in vitro experiments or animal models, and more in vivo experiments are needed to explore their specific molecular mechanisms. In addition, the synergistic antioxidant mechanism of SeNPs with other antioxidants requires further study.
Inflammation is a common pathological process in many diseases. Usually, the inflammatory response prompts the body to release a large amount of chemokines and pro-inflammatory factors, such as IFN-γ, IL-6, TNF-α, NF-κB, and COX-2. An appropriate inflammatory response is beneficial for forming a protective barrier to resist external stimuli and helping repair damaged areas, but excessive and persistent inflammatory responses will instead damage tissues and cause systemic side effects.
Epidemiological and clinical studies have shown that selenium deficiency is closely related to a variety of inflammatory-related diseases, and low selenium levels often aggravate inflammatory responses and organ damage.78 In most inflammatory diseases, SeNPs significantly inhibit and reduce the expression of TNF-α, IFN-γ, IL-12, IL-2, IL-1β, IL-6, COX-2, and NF-κB, and their anti-inflammatory mechanisms mainly include inhibiting the phosphorylation and degradation of IκB-α required for NF-κB activation, thereby reducing the transcription of pro-inflammatory cytokine genes.79,80
SeNPs exert systematic immune regulatory effects at both the innate and adaptive immunity levels by acting on various immune cells (macrophages, dendritic cells, NK cells, T cells).81 Macrophages are the first line of defense in innate immunity. SeNPs enhance phagocytosis, autophagy, antigen presentation, and pathogen clearance by inducing M1 polarization of macrophages. NK cells are important effector cells in innate immunity.
SeNPs enhance immunotherapy by promoting the proliferation and activation of NK cells. Dendritic cells present antigens to guide T cell differentiation. SeNPs promote the maturation of dendritic cells to connect innate and adaptive immunity.
T cells are the core of adaptive immunity. SeNPs enhance T cell response by promoting the proliferation of CD4⁺ T cells and Th1 differentiation, and enhancing the function of CD8⁺ T cells. The key signaling pathways involved in immune regulation by SeNPs include the ROS-mitochondria pathway, PI3K/AKT/mTOR pathway, NF-κB pathway, p53 pathway, MAPK/caspase-3 pathway, and TRAIL/FASL signaling pathway.81
Currently, these functions of SeNPs have been specifically demonstrated in the treatment of NAFLD and AS. In the AS model, oral administration of BSA-SeNPs (50 μg Se/kg/day) for 8 weeks significantly increased serum NO levels by restoring endothelial function and enhanced GSH-Px, SOD, and catalase activities.82 Meanwhile, SeNPs maintained the balance between pro-inflammatory and anti-inflammatory immune responses by reducing the expression of vascular inflammation markers (VCAM-1, ICAM-1) and decreasing circulating pro-inflammatory cytokines (TNF-α, IL-6) in the AS model. Similarly, in the NAFLD model, CS-SeNPs reduced hepatic lipid peroxidation (MDA) levels and restored SOD and GSH activities.83 Meanwhile, SeNPs significantly reduced the levels of TNF-α, IL-1β, and IL-6 in the liver of NAFLD mice, thereby slowing the progression from steatosis to steatohepatitis.
Research and Progress of SeNPs in AS and NAFLD
As mentioned above, these functions of SeNPs are closely related to the pathogenesis of AS and NAFLD. Therefore, SeNPs can improve the progression of AS and NAFLD through these functions. Early studies have generally demonstrated the short-term beneficial effects of SeNPs against AS (Figure 7).
In the AS model, Guo L et al found that bovine serum albumin (BSA)-SeNPs (50 μg Se/kg/day, 8 weeks) significantly reduced the levels of TC (40.67 ± 6.15 mmol/L → 20.70 ± 3.28 mmol/L), TG (4.03 ± 0.77 mmol/L → 2.32 ± 0.21 mmol/L), and LDL-C (11.08 ± 0.38 mmol/L → 4.37 ± 1.13 mmol/L), and increased the levels of HDL-C (0.70 ± 0.18 mmol/L → 1.24 ± 0.25 mmol/L), GSH-Px (207.00 ± 51.16 U/mL → 408.00 ± 78.12 U/mL), and SOD (71.35 ± 1.38 U/mL → 83.78 ± 4.85 U/mL).82 Consistent with this result, Xiao et al further confirmed that BSA-SeNPs (50 μg Se/kg/day, 12 weeks) significantly reduced the levels of TC (51.64 ± 5.02 mmol/L → 33.13 ± 3.57 mmol/L), TG (2.01 ± 0.36 mmol/L → 1.15 ± 0.21 mmol/L), and LDL-C (11.85 ± 0.72 mmol/L → 8.41 ± 0.27 mmol/L), and increased the levels of HDL-C (0.36 ± 0.10 mmol/L → 1.02 ± 0.21 mmol/L), GSH-Px (128.00 ± 23.76 U/mL → 360.00 ± 87.00 U/mL), and SOD (138.61 ± 5.61 U/mL → 156.59 ± 14.43 U/mL) in the AS model.27 Furthermore, another study compared the effects of chitosan (CS)-SeNPs (40 μg Se/kg/day) and Na2SeO3 (40 μg Se/kg/day) in the early stage of AS. The results showed that both CS-SeNPs and Na2SeO3 significantly reduced the area of aortic plaques (25.1% and 38.6%) after 10 weeks of administration. It is notable that CS-SeNPs showed lower cytotoxicity in vitro than Na2SeO3.84 Interestingly, Xiao J et al found that long-term administration of SeNPs not only failed to improve AS but significantly exacerbated the formation of AS.
They fed AS mice with low-dose SeNPs for 24 weeks. Surprisingly, SeNPs increased the area of aortic plaques (31.16 ± 1.29% → 58.83 ± 5.27%).85 This strongly suggests that the safety window of SeNPs is not a fixed value but is closely related to the dosing cycle and cumulative dose. Short-term supplementation with SeNPs may exert antioxidant protective effects by inducing the rapid synthesis of GSH-Px, but long-term continuous intake may lead to saturation of the body’s selenium levels.
Subsequently, excessive selenium may exert a pro-oxidative effect, exacerbating oxidative damage. To overcome the challenges and difficulties of SeNPs in AS, researchers have begun to explore targeted delivery strategies based on SeNPs. Wang et al linked Oligodeoxynucleotide (A151) and LacNAc (LN) to the surface of SeNPs.
In ApoE−/− mice, LN-A151-SeNPs significantly inhibited the phenotypic transformation of vascular smooth muscle cells into macrophage-like cells. Mechanistically, LN-A151-SeNPs reduced the maturation and secretion of IL-1β by inhibiting the activation of the NLRP3 inflammasome. Meanwhile, LN-A151-SeNPs effectively cleared ROS by upregulating the expression and activity of various selenium proteins.30 Yin et al utilized the natural affinity of platelet membranes for atherosclerotic plaques to prepare a platelet membrane biomimetic nanodelivery system (PM@Se/Rb1 NPs) that encapsulates ginsenoside Rb1 and SeNPs.
In ApoE−/− mice, the PM@Se/Rb1 NPs significantly reduced the plaque area of the aortic arch (85 → 20%) and aortic root (79 → 26.5%).86Figure 7Therapeutic efficacy and mechanism of SeNPs in AS. SeNPs improved the progression of AS by up-regulating the expression of HDL-C, NO, GSH-PX, SOD, CAT and down-regulating the expression of TC, TG, LDL-C, NLRP3, IL-1β, ROS, and ICAM-1. Figure generated with BioRender.com.A schematic infographic of atherosclerosis stages and SeNP effects on risk factors and biomarkers.Schematic infographic with headings, Dyslipidemia, Hypertension, Diabetes, Genetic factors, leading to, Atherosclerosis progression.
A sequence of artery cross sections is labeled, Initial lesion, Fatty streak, Atheroma, Fibrous plaque, Complicated lesion. Biomarker groups show direction arrows: TC down, NO up, NLRP3 down; TG down, GSH PX up, IL 1 beta down; LDL C down, SOD up, ROS down; HDL C up, CAT up, ICAM 1 down. A sphere labeled, SeNPs, points toward the biomarker groups.
Bullet list: BSA SeNPs left parenthesis 50 microgram Se per kilogram per day, 8 weeks slash 12 weeks right parenthesis; CS SeNPs left parenthesis 40 microgram Se per kilogram per day, 10 weeks slash 12 weeks right parenthesis; LN A151 SeNPs left parenthesis 0.10 milligram per kilogram twice per week, 8 weeks right parenthesis.Notes: ↑, upregulation or increase; ↓, downregulation or decrease.
In recent years, a series of studies have revealed the beneficial effects of SeNPs on NAFLD (Figure 8). In an in vitro study, CS-SeNPs significantly reduced free fatty acids-induced lipid deposition and reversed the inhibitory effect of free fatty acids on the autophagy process. The inhibition of autophagy leads to an increase in lipid deposition and the levels of TC and TG, as well as a decrease in the expression levels of genes related to fat metabolism.
In an in vivo study, CS-SeNPs improved liver function, serum lipids, oxidative stress and inflammation in NAFLD.83 Another similar study investigated the beneficial effects of low-molecular-weight chitosan-selenium nanoparticles (LCS-SeNPs) on NAFLD. The research results indicated that LCS-SeNPs (200 mg/kg/day) not only inhibited fat accumulation but also reshaped the composition of the intestinal microbiota and improved intestinal barrier function.28 Zhang Z et al synthesized novel SeNPs using Lactobacillus coryniformis ES23 (L. coryniformis ES23). They found that SeNPs (7.5 mg/kg/week) could significantly alleviate cholestasis, inflammation and fibrosis.
Mechanistically, SeNPs regulated fatty acid and TG metabolism through the PPARα pathway. Additionally, SeNPs reduced iron accumulation and inhibited ferroptosis in the liver of mice by decreasing the expression of HMOX1 and TFRC.87 Another similar study involved the synthesis of novel SeNPs using Lactobacillus acidophilus HN23. This study indicated that SeNPs alleviated NAFLD by reducing lipid deposition and oxidative damage in liver cells.88 As common environmental pollutants in daily life, polystyrene microplastics (MPs) can cause liver damage.
Shen Q et al synthesized novel SeNPs using Bacillus cereus derived from yak (YC-3-SeNPs). They found that YC-3-SeNPs (1 mg/kg/day, 28 days) significantly alleviated MPs-induced NAFLD. Mechanistically, YC-3-SeNPs activated the PPARα signaling pathway and the NRF2 signaling pathway.89Figure 8Therapeutic efficacy and mechanism of SeNPs in NAFLD.
SeNPs improved the progression of NAFLD by up-regulating the expression of GSH, SOD, CAT and down-regulating the expression of TNF-α, IL-6, TGF-β, HΜOX1, TFRC, ALT, AST, ALP, TC, TG, LDL-C. Figure generated with BioRender.com.Flow diagram of SeNPs acting on NAFLD progression with liver stages and up or down biomarker arrows.Non alcoholic fatty liver disease progression diagram from risk factors to liver stages, with SeNPs linked to biomarker changes. Top row shows Dyslipidemia, Obesity, Diabetes and Genetic factors, with a downward arrow to the text, Non alcoholic fatty liver disease progression, above a right pointing arrow.
Along the arrow are five liver icons labeled, Liver, NAFL, NASH, Fibrosis and liver cirrhosis. Below, a central upward arrow points toward NASH from biomarker boxes. Down arrows are shown next to TNF dash alpha, IL dash 6, TGF dash beta, HMOX1, TFRC, ALT, AST, ALP, TC, TG and LDL dash C.
Up arrows are shown next to SOD, CAT and GSH. A sphere labeled, SeNPs, sits below with an upward arrow toward the biomarker boxes.Notes: ↑, upregulation or increase; ↓, downregulation or decrease.
Safety and Toxicological Considerations of SeNPs
Despite the promising therapeutic efficacy of SeNPs, their clinical translation necessitates rigorous safety evaluation. The toxicity of selenium is fundamentally dose-dependent and influenced by physicochemical properties (size, surface charge, stabilizer coating). Stepankova et al systematically evaluated the toxicological properties of SeNPs with different morphologies and aspect ratios.
They found that high aspect ratio selenium nanorods (AR ≈ 22.3) exhibited significant cytotoxicity against healthy cells and induced kidney damage in mice, whereas low aspect ratio nanorods (AR ≈ 11.5) showed optimal biocompatibility.90 In a comparative toxicological assessment, the acute oral LD50 of Sargassum fusiforme polysaccharide-modified SeNPs was 88.76 mg Se/kg, while the 28-day repeated-dose NOAEL of Na2SeO3 was 4.43 mg Se/kg. This indicated that SeNPs effectively reduced the acute toxicity of selenium.6 However, long-term administration of low-dose SeNPs aggravated cardiovascular toxicity in ApoE−/− mice.85 In zebrafish embryos, bare SeNPs induced coagulation at 1.56 μg/mL. In contrast, CS-SeNPs showed no coagulation up to 25 μg/mL, highlighting the critical role of surface modification in mitigating toxicity.91 Regrettably, no human clinical trials have evaluated SeNP pharmacokinetics, biodistribution, or maximum tolerated dose in AS or NAFLD populations.
Future studies must establish standardized toxicological databases to define the safe dose ranges, treatment cycles, and particle size specifications for chronic disease indications.
Discussion
Although several studies have demonstrated the beneficial effects of SeNPs in NAFLD and AS (Table 3), we cannot overlook the limitations of these studies. The main limitations of the current study include manufacturing challenges, regulatory considerations, and clinical translation barriers. In terms of manufacturing challenges, chemical synthesis usually requires the use of toxic solvents and has high production costs, while biological synthesis has problems of low yield and long fermentation times.
Moreover, the lack of standardization in the production process further exacerbates these manufacturing challenges. In terms of regulatory considerations, SeNPs occupy a nebulous space between a dietary supplement (selenium) and a novel nanomedicine, creating significant ambiguity in classification. Moreover, the “nanomaterial” designation triggers additional scrutiny (physicochemical characterization, impurity profiling, environmental impact), which is not typically required for conventional drugs.
The major barriers preventing clinical translation of SeNPs include the lack of long-term safety data, unclear pharmacokinetic characteristics, insufficient clinical relevance of animal models, poor scalability of the targeted delivery system, and the absence of reliable efficacy biomarkers. Among them, the limitation of animal models is a problem that urgently needs to be solved. On the one hand, the animal models used in most studies cannot fully replicate the complex metabolic and immune characteristics of human patients.
Moreover, the induction period of these AS or NAFLD models is relatively short (8–24 weeks), while the progression of human diseases is much longer. On the other hand, most studies administer the drugs by intraperitoneal injection or oral gavage, bypassing the natural gastrointestinal absorption and first-pass metabolism processes that occur in the human body. Therefore, conducting large-scale clinical studies in the future and emphasizing systematic reviews or meta-analyses will further enhance translational relevance and maintain balance.
Table 3Summary of SeNPs in AS and NAFLD ModelsFormulationLigandSynthesis MethodSize (nm)Zeta PotentialDiseaseShapeMechanismOutcomeRef.BSA-SeNPsBSAChemical synthesis37.2/ASSpherical↓TC, ↓TG, ↓LDL-C, ↑HDL-C, ↑GPx/SOD/CATImprovement[82]BSA-SeNPsBSAChemical synthesis38.5NegativeASSpherical↓Plaque area, ↓Hepatic cholesterol synthesis, ↑Antioxidant activityImprovement[27]CS-SeNPsCSChemical synthesis65.8PositiveASSpherical↓Plaque area, ↑Antioxidant activity, ↑Anti-inflammationImprovement[27]CS-SeNPsCSChemical synthesis73.432.1 mVASSpherical↓NF-κB, ↓VCAM-1/ICAM-1/E-selectinImprovement[84]LN-A151-SeNPsA151 + LacNAcChemical synthesis88.9 ± 1.45−21.1 ± 1.5 mVASSpherical↓Plaque area, ↓NLRP3 inflammasome, ↑SelenoproteinsImprovement[30]PM@Se/Rb1 NPsPM+ Ginsenoside Rb1Chemical synthesis60−15.2 mVASSpherical↓Plaque area, ↓ICAM-1, ↑Anti-inflammationImprovement[86]CS-SeNPsCSChemical synthesis64.65 ± 6.5825 mVNAFLDSpherical↓Hepatic lipid deposition, ↑AutophagyImprovement[83]LCS-SeNPsLCSChemical synthesis//NAFLDSpherical↓Hepatic lipid deposition, ↑Mucin-associated microbiota, ↑Gut barrier improvementImprovement[28]L. coryniformis ES23-SeNPsL. coryniformis ES23Biological synthesis (bacterial)127.4 ± 41.2−35.0 ± 6.3 mVNAFLDSpherical↓Inflammation, ↓Fibrosis, ↓HMOX1/TFRC, ↑PPARαImprovement[87]YC-3-SeNPsYC-3Biological synthesis (bacterial)100-200/NAFLDSpherical↓Hepatic lipid deposition, ↓Liver injury, ↑PPARαImprovement[89]Notes: ↑, upregulation or increase; ↓, downregulation or decrease.
We believe that future research should focus on the following directions: (1) Standardization of nanoparticle synthesis: The standardization of nanoparticle synthesis is critical to ensure batch-to-batch consistency and product reproducibility, thereby satisfying regulatory requirements for pharmaceutical quality control. (2) Pharmacokinetic studies: Comprehensive pharmacokinetic studies are indispensable for elucidating the absorption, distribution, metabolism, and excretion of SeNPs, which form the pharmacological basis for rational dose regimens. (3) Safety profiling: Rigorous safety profiling is essential to define the therapeutic window and mitigate the risk of chronic toxicity.
(4) Large-animal validation: Large-animal validation bridges the gap between rodent studies and human applications, enhancing the predictive value of preclinical efficacy and safety data. (5) Well-designed clinical trials: Well-designed clinical trials are the ultimate gateway to confirm therapeutic benefit and establish evidence-based clinical guidelines. (6) Regulatory approval challenges: Regulatory approval challenges are imperative to create a clear and feasible pathway toward clinical market entry.
Conclusion
In conclusion, the beneficial effects of SeNPs in AS and NAFLD have been widely verified. The core data and results include the following points: (1) In the AS model, BSA-SeNPs (50 μg Se/kg/day, 8 weeks and 12 weeks) significantly reduced the levels of TC (40.67 ± 6.15 mmol/L → 20.70 ± 3.28 mmol/L, 51.64 ± 5.02 mmol/L → 33.13 ± 3.57 mmol/L), TG (4.03 ± 0.77 mmol/L → 2.32 ± 0.21 mmol/L, 2.01 ± 0.36 mmol/L → 1.15 ± 0.21 mmol/L), and LDL-C (11.08 ± 0.38 mmol/L → 4.37 ± 1.13 mmol/L, 11.85 ± 0.72 mmol/L → 8.41 ± 0.27 mmol/L), and increased the levels of HDL-C (0.70 ± 0.18 mmol/L → 1.24 ± 0.25 mmol/L, 0.36 ± 0.10 mmol/L → 1.02 ± 0.21 mmol/L), GSH-Px (207.00 ± 51.16 U/mL → 408.00 ± 78.12 U/mL, 128.00 ± 23.76 U/mL → 360.00 ± 87.00 U/mL), and SOD (71.35 ± 1.38 U/mL → 83.78 ± 4.85 U/mL, 138.61 ± 5.61 U/mL → 156.59 ± 14.43 U/mL). (2) In the AS model, CS-SeNPs (40 μg Se/kg/day, 10 weeks) significantly reduced the area of aortic plaques (25.1%).
Similarly, PM@Se/Rb1 NPs significantly reduced the plaque area of the aortic arch (85 → 20%) and aortic root (79% → 26.5%). Paradoxically, a study found that SeNPs increased the area of aortic plaques (31.16 ± 1.29%→58.83 ± 5.27%). (3) In the NAFLD model, various SeNPs reduced the area of steatosis, reduced the levels of TC, TG, ALT, and AST, and inhibited inflammation, oxidative stress, and the progression of fibrosis.
In summary, as a nanomaterial with multi-target regulation functions, SeNPs have great potential in the treatment of AS and NAFLD.