The antioxidant effect of luteolin is one of its most well-known pharmacological properties. The production of free radicals is closely related to oxidative stress damage, which is considered an important trigger for various chronic diseases and the aging process (Teleanu et al., 2022; Forman and Zhang, 2021). Research has shown that luteolin effectively removes free radicals generated in the body and enhances the cell’s own antioxidant capacity, thereby reducing the impact of oxidative damage on cells. Specifically, luteolin activates the antioxidant enzyme system, such as superoxide dismutase (SOD) and glutathione peroxidase (GPx), enhancing the cell’s defense mechanism and providing a stronger protective barrier (Gu et al., 2024). This characteristic has attracted significant attention in research related to cardiovascular diseases, diabetes, and neurodegenerative diseases (Chagas et al., 2022).

Luteolin also exhibits significant anti-inflammatory effects. During the process of chronic inflammation, the abnormal release of cytokines plays an important role, with increased levels of pro-inflammatory factors such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) leading to various pathological states in the body. Luteolin can effectively alleviate local and systemic inflammatory responses by inhibiting the secretion of these cytokines (Aziz et al., 2018). Some studies suggest that luteolin may suppress the expression of inflammation-related genes by regulating the nuclear factor kappa B (NF-κB) signaling pathway, thereby reducing the release of inflammatory mediators, which has potential therapeutic value for diseases such as rheumatoid arthritis and inflammatory bowel disease (Caporali et al., 2022; Conti et al., 2021).

The anticancer effect of luteolin has attracted widespread attention from research ers in recent years. Multiple experimental results show that luteolin can induce apoptosis in various cancer cells (such as breast cancer, colon cancer, and lung cancer) and inhibit their proliferation (Zhang et al., 2006). The mechanism of this effect may involve the regulation of multiple cell signaling pathways, including the upregulation of pro-apoptotic genes and downregulation of anti-apoptotic gene expression (Lee et al., 2012). Additionally, luteolin may also play an important auxiliary role in anticancer therapy by inhibiting the migration and invasion capabilities of tumor cells, thereby reducing the risk of metastasis (Ashrafizadeh et al., 2020).

Previous studies have shown that luteolin has significant cardiovascular protective effects (Luo et al., 2017). In recent years, increasing evidence supports the mechanism by which luteolin prevents cardiovascular diseases by improving endothelial function and reducing low-density lipoprotein cholesterol (LDL-C) levels (Fikry et al., 2024). First of all, endothelial cells play a crucial role in cardiovascular health. Normal endothelial function helps maintain the balance of vasodilation and vasoconstriction, regulates blood pressure, and prevents the occurrence of atherosclerosis. Studies have shown that luteolin can enhance the synthesis and release of nitric oxide (NO) in endothelial cells, promoting vasodilation, thereby improving microcirculation and reducing the risk of cardiovascular diseases. In addition, luteolin can also inhibit the inflammatory response of endothelial cells, further protecting the integrity of the vascular endothelium and lowering the incidence of cardiovascular diseases (Wang et al., 2023). At the same time, high levels of LDL cholesterol are considered an important risk factor for cardiovascular diseases. Luteolin effectively lowers LDL cholesterol levels by influencing cholesterol metabolism, particularly by regulating the liver’s absorption and excretion of cholesterol (Orrego et al., 2009). Additionally, luteolin may also reduce oxidative stress through its antioxidant properties, which is particularly important for preventing arterial damage caused by high cholesterol. Therefore, the application of luteolin is seen as a promising strategy for improving cholesterol levels and reducing the risk of cardiovascular diseases.

However, the bioavailability of luteolin is relatively low, which limits its effectiveness in clinical applications. To address this issue, the application of nanocomposites has emerged. Nanotechnology can enhance the accumulation concentration of drugs in specific tissues, thereby improving their bioavailability and efficacy. By encapsulating luteolin in nanocarriers, its concentration in cardiac tissue can be significantly increased (Pechanova et al., 2020). This not only enhances the cardioprotective effects of luteolin but also provides new ideas and directions for the treatment of cardiovascular diseases.

Luteolin-based nanocomposites have shown remarkable efficacy in cancer treatment. Previous studies have demonstrated that luteolin, as an active ingredient, effectively inhibits tumor cell growth by inducing apoptosis and suppressing angiogenesis (Lin et al., 2008). The use of nanocarrier technology significantly enhances the targeted delivery of luteolin, simultaneously reducing damage to normal tissues. The nano-formulations also exhibit multifaceted synergistic effects in cancer therapy research, primarily through mechanisms such as enhancing chemotherapeutic efficacy, remodeling the tumor immune microenvironment, reversing drug resistance, and inhibiting tumor angiogenesis (Wang et al., 2021). Research on these nanocomposites offers new perspectives and possibilities for developing safer and more effective cancer treatment strategies.

Fu et al. prepared ROS-responsive resveratrol nano-composites using the double emulsion solvent volatilization method, LUT@PPS-PEG nano-composites, with a particle size of 169.77 ± 7.33 nm (Fu et al., 2023). The drug delivery material in this system is the common reactive oxygen species-responsive material Poly (propylene sulfide)-poly (ethylene glycol) (PPS-PEG). In vitro release experiments showed that LUT@PPS-PEG could indeed achieve ROS-responsive release of resveratrol (Figure 1). In further pharmacological experiments, LUT@PPS-PEG nano-composites were effectively taken up by SK-MEL-28 cells and significantly inhibited their proliferation and migration. Animal experiments also demonstrated good anti-melanoma effects (Fu et al., 2023).

Wu et al. designed and prepared folacin-modified luteolin-loaded nanocomposites, Luteolin/Fa-PEG-PCL, for glioma therapy (Wu et al., 2019). This drug delivery system uses folic acid modified poly (ethylene glycol)-poly (ε-caprolactone) (Fa-PEG-PCL) nano-micelles to encapsulate luteolin (Figure 2). The modification with folic acid is able to increase tumor cell uptake of this nanomedicine, thereby enhancing targeting specificity and improving efficacy. Subsequent in vitro and in vivo experiments demonstrated that Luteolin/Fa-PEG-PCL significantly inhibited the proliferation of GL261 cells and induced apoptosis. In animal experiments, it was found that Luteolin/Fa-PEG-PCL accumulated at the glioma site and significantly inhibited glioma growth. In another study focusing on glioma, Zheng et al. designed and prepared luteolin-loaded MPEG-PCL nanomicelles. These nanomicelles significantly improved the solubility and bioavailability of luteolin, and achieved sustained release of the compound. They further validated the anti-tumor effects of this formulation at the cellular and animal levels, showing that compared to free luteolin, luteolin-loaded MPEG-PCL nanomicelles could more effectively induce apoptosis in C6 and U87 cells and inhibit neovascularization in tumor tissues. Additionally, further cell experiments indicated that these nanomicelles induced apoptosis in tumor cells through downregulation of Pro-caspase9 and Bcl-2 and upregulation of cleaved-caspase9 and Bax via the mitochondrial pathway. Animal distribution experiments demonstrated that luteolin-loaded MPEG-PCL nanomicelles could accumulate in tumor tissues, achieving tumor targeting (Wu et al., 2019).

In a therapeutic study targeting breast cancer, Wang et al. designed and prepared f olic acid-modified ROS-responsive nanoparticles for targeted delivery of luteolin, based on the characteristics of high levels of ROS in the tumor microenvironment and high expression of folate receptors on tumor cells (Wang et al., 2021). They first synthesized ROS-responsive materials (Oxi-aCD) and then obtained core-shell nanoparticles using a nanoprecipitation/self-assembly method. These were further modified with DSPE-PEG-FA to obtain the final nanocomposite Lut/FA-Oxi-aCD. The nanocomposite had a relatively uniform particle size of 196.7 nm. In drug release experiments, results showed that this system could achieve ROS-responsive release of luteolin. Subsequent cell experiments demonstrated that Lut/FA-Oxi-aCD was efficiently internalized by 4T1 cells and significantly inhibited their proliferation. Final animal experiments also proved that Lut/FA-Oxi-aCD possessed long circulation and tumor-targeting properties, with significant tumor inhibition effects (Wang et al., 2021). As shown in Table 1, we have summarized the recent research applications and associated functional properties of luteolin nanoformulations in cancer therapy.

Diabetes has become an increasingly severe health issue worldwide, with its incidence continuously rising (Glovaci et al., 2019). In addition to classic metabolic disorders, there is growing evidence indicating a significant association between diabetes and neurological diseases (Campayo et al., 2011). In particular, the common occurrence of brain inflammation in diabetic patients has drawn widespread attention from researchers. This neuroinflammation may not only affect cognitive function but also exacerbate patients’ conditions by promoting the development of neurodegenerative diseases (Chong et al., 2024; Kopp et al., 2022). Regarding this situation, Moustafa et al. developed a ZnO nanoformulation loaded with luteolin that can attenuate neuroinflammation associated with diabetes, and used this formulation to treat a diabetic rat model. The results show that luteolin/ZnO nanoparticles can reduce lipid peroxidation, increase antioxidant enzyme activity, and decrease inflammation under oxidative stress. Therefore, they can lower hyperglycemia, enhance insulin levels, and improve insulin resistance. In addition, luteolin/ZnO nanoparticles upregulate miR-124, decrease C/EBPA mRNA, increase Bcl-2, and inhibit apoptosis. The results suggest that diabetes increases blood-brain barrier permeability through the downregulation of tight junction proteins, a phenomenon that is restored following treatment with luteolin/ZnO nanoparticles. Luteolin/ZnO nanoparticles target C/EBPA to regulate miR-124 and microglial cell polarization, and alleviate inflammatory damage by modulating oxidative stress-sensitive signaling pathways. Luteolin/ZnO nanoparticles present a novel therapeutic target for protecting the blood-brain barrier and preventing diabetic neurovascular complications (Moustafa et al., 2023).

Parra et al. synthesized selenium nanoparticles co-loaded with diosmin and luteolin (LU/DIO-SeNPs), with an average particle size of 47.84 nm (Gutiérrez et al., 2022). They subsequently applied this nanomedicine for the treatment of streptozotocin-induced diabetic mice. Compared to STZ-induced untreated diabetic mice, significant changes were observed in body weight, food intake, and water consumption. Additionally, LU/DIO-SeNPs exhibited strong antioxidant activity, as evidenced by the detection of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the liver and kidneys. These nanoparticles also demonstrated a preventive effect against liver damage, assessed through the activity of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). The nanospheres showed remarkable antidiabetic activity, with a synergistic effect between selenium and flavonoids. This study presents a novel type of SeNPs nanosphere prepared using an efficient strategy, designed to incorporate rutin and quercetin to enhance the efficacy against type 2 diabetes (Gutiérrez et al., 2022).

Diabetic ureteral injury is a relatively rare but clinically significant complication that is closely associated with the long-term hyperglycemic state in diabetic patients (Yuan et al., 2023). This condition is usually caused by microvascular and neuropathic changes due to diabetes, which significantly affect the structure and function of the urinary system. The pathogenesis of diabetic ureteral injury mainly involves vascular endothelial damage and nervous system impairment induced by hyperglycemia. Chronic hyperglycemia can lead to thickening of the microvascular basement membrane and dysfunction of vascular endothelial cells, resulting in insufficient local blood supply. Additionally, diabetes can cause autonomic neuropathy, affecting the peristaltic function of the ureter, leading to urine retention or reflux, thereby increasing the risk of urinary tract infections and chronic kidney damage (Agashe and Petak, 2018). Moreover, oxidative stress under hyperglycemic conditions can directly damage the epithelial cells of the ureter (Jolivalt et al., 2016). Jing et al. prepared selenium nanoparticles loaded with luteolin (Luteolin-SeNPs) and used them for the treatment study of diabetic ureteral injury. Cytotoxicity assays on HEK 293 and NIH-3T3 showed >90% cell viability, demonstrating excellent biocompatibility of the formulation. Further research has shown that Luteolin-SeNPs can inhibit the NLRP3(NOD-like receptor family pyrin domain containing 3) inflammasome through the Nrf2/ARE pathway, which is beneficial for the treatment of diabetic ureteral injury. The developed luteolin-SeNPs may become an effective formulation for the treatment of diabetic ureteral injury (Jing et al., 2024).

The pathogenesis of neurodegenerative diseases is complex, and there is currently no effective cure (Temple, 2023; Chi et al., 2018). Therefore, finding novel and effective therapeutic strategies is of paramount importance. Luteolin, with its unique biochemical properties and multiple biological activities, has become a research hotspot in this field. Luteolin, a flavonoid compound, exerts neuroprotective effects through various mechanisms (He et al., 2023). On the one hand, it can reduce intracellular reactive oxygen species (ROS) through its antioxidant activity, thereby mitigating oxidative stress-induced damage to neural cells (Jayawickreme et al., 2024). On the other hand, luteolin can inhibit neuroinflammatory responses, regulate intracellular signaling pathways, and promote the release of neurotrophic factors, thus preserving neuronal function (Kempuraj et al., 2021). Furthermore, luteolin has been found to inhibit the aggregation of β-amyloid proteins, an action of significant importance in the prevention and treatment of Alzheimer’s disease (Younis et al., 2024).

AD is often characterized by the advanced deterioration of cognition and memory, and it accounts more than 60% of most dementia cases (Scheltens et al., 2021). The presence of oxidative stress markers is one of the earliest changes that occur in the brains of individuals with AD (Bai et al., 2022; Chen and Zhong, 2014). As mentioned earlier, luteolin has various activities such as antioxidant properties, and thus it is gaining more attention in the treatment of AD. However, due to the presence of the blood-brain barrier, enhancing the concentration of luteolin within the brain is a major challenge for its clinical application (Passeri et al., 2022). To address this, Abbas et al. designed and prepared novel luteolin-loaded chitosan-decorated nanoparticles that can target the brain. Behavioral studies indicate significant improvement in the acquisition of both short-term and long-term spatial memory in mice. Furthermore, histological assessments reveal increased neuronal survival rates and a reduction in the number of amyloid plaques. Biochemical results demonstrate enhanced antioxidant effects and reduced levels of pro-inflammatory mediators. Additionally, compared with the model control group, the reduction in Aβ aggregation and hyperphosphorylated tau protein levels reached 50%, further confirming the ability of luteolin-loaded chitosan nanoparticles (LUT-CHS) to alleviate pathological changes associated with AD (Abbas et al., 2022).

In another study on AD treatment, Elsheikh et al. developed via Intranasal Luteolin-Loaded Nanobilosomes. The Nanobilosomes were prepared using the thin-film hydration technique, with a particle size of 153.2 ± 0.98 nm, and a loading efficiency of Luteolin reaching 70.4% ± 0.77%. The in vivo therapeutic effect experiment was conducted on AD mice models, which was established via intracerebroventricular injection of 3 mg/kg of streptozotocin. Behavioral, biochemical, histological, and immunohistochemical experiments were performed after 21 days of intranasal inhalation of luteolin bilosomes or luteolin suspensions (50 mg/kg). The luteolin bilosomes improved short-term and long-term spatial memory and also showed antioxidant properties, reducing the levels of pro-inflammatory mediators. They also inhibited the aggregation of amyloid βand the overphosphorylation of Tau proteins in the hippocampus. Compared to luteolin suspension, luteolin bilosomes represent an effective, safe, non-invasive approach with superior cognitive function (Elsheikh et al., 2022).

Luteolin nanocomposites, as a novel drug carrier, have demonstrated broad application prospects in disease treatment. In addition to their performance in the aforementioned diseases, they have also shown good effects in the treatment of diabetes, liver diseases, and immune system disorders.