Unveiling the Potential of Quercetin: Chemistry, Health Benefits, Toxicity, and Cutting-Edge Advances

Abstract

Quercetin, a naturally occurring flavonoid, has gained significant attention in recent years due to its potential health benefits and versatile applications. This book chapter explores the chemistry of quercetin, shedding light on its molecular structure, biosynthesis, and extraction methods. The chapter delves into the extensive research on the health effects of quercetin, highlighting its antioxidant, anti-inflammatory, anticancer, neuroprotective, and cardioprotective properties. Moreover, the potential risks and toxicity associated with quercetin consumption are thoroughly examined, emphasizing the importance of proper dosage and potential drug interactions. The chapter concludes by providing an overview of recent advances in quercetin development, including nanoformulations, targeted delivery systems, and combination therapies, that hold promise for enhancing its therapeutic efficacy and bioavailability. This comprehensive exploration of quercetin aims to provide researchers, scientists, and healthcare professionals with valuable insights into its multifaceted nature and potential applications in human health.

1. Introduction

1.1 Overview of quercetin: Definition and significance

Quercetin is a natural compound belonging to the flavonoids family; it is widely distributed in the plant kingdom and has been isolated from many edible and non-edible plants. Quercetin has several pharmacological properties, making it a promising candidate for many pharmaceutical formulations. Nutritionally, quercetin is a major component of the human diet. Onions are the main source of quercetin, in addition to some other plant species such as apples, buckwheat, grapes, tea, cherries, tomatoes, mangoes, citrus, and plums [1, 2].

From the chemical point of view, quercetin is a plant pigment with a flavonol-type structure called 3,3,4,5,7-pentahydroxyflavone and 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one) according to IUPAC. It has a molecular formula (C₁₅H₁₀O₇) and a molecular weight (302.236 g/mol) [3]. The main structure of the compound is a 15-carbon skeleton, comprising two benzene rings labeled (A-ring and B-ring) connected by a 3-carbon heterocyclic ring labeled (C-ring), in addition to five hydroxyl functional groups [4]. However, the B-ring is considered the main participant in its potent antioxidant activity because it contains a heavy hydroxylation pattern that enables the compound to be a strong free radicals scavenger [5].

On the other side, the compound showed a broad spectrum of biological activities such as anti-SARS-CoV-2, antioxidant, antidiabetic, anticancer, antiarthritic, antiaging, anti-Alzheimer’s, antiviral, anti-inflammatory, antimicrobial, anti-allergic, anti-obesity, cardiovascular, hepatoprotective, neuroprotective, and wound-healing [2].

1.2 Historical context and contemporary interest

First identified in 1854 from its glycosidic form, quercitrin, quercetin—named after the Latin word “Quercetum” for Oak Forest—has become a significant compound in pharmaceuticals, cosmetics, and food production [6]. It is predominantly found in a range of health foods and herbal products, with a daily intake ranging from 5 to 40 mg, reflecting its extensive metabolism in the intestine and liver [7, 8]. Quercetin’s hydrophilic, stable, and bioavailable characteristics are notably enhanced through glycosylation.

This chapter, “Unveiling the Potential of Quercetin: Chemistry, Health Benefits, Toxicity, and Cutting-Edge Advances,” explores quercetin’s chemical makeup, therapeutic attributes, and the latest research innovations. It highlights quercetin’s role as a cornerstone in the study of plant-based compounds and their impact on human health. Acknowledged for its antioxidant, anti-inflammatory, anticancer, neuroprotective, and cardioprotective properties, quercetin is a ubiquitous dietary component vital for both nutrition and therapy.

The narrative details quercetin’s historical progression, its natural synthesis, extraction methods, and the strides made in understanding its complex therapeutic utility. It covers quercetin’s chemical structure, emphasizing its distinctive flavonol skeleton and the impact of its hydroxylation on antioxidant activities.

In addressing health implications, the chapter outlines quercetin’s mechanisms of action—ranging from disease prevention to managing cardiovascular health, cancer, diabetes, mental health, and neurodegenerative disorders. It also critically assesses the safety and potential risks of quercetin, particularly at high doses, and its interactions with medications, underscoring the importance of cautious supplementation.

Looking to the future, the chapter delves into innovative delivery systems and combination therapies that enhance quercetin’s therapeutic potential. It discusses advances in nanotechnology and targeted delivery that aim to improve solubility and bioavailability, positioning quercetin at the forefront of scientific exploration and therapeutic innovation.

Overall, the chapter provides a comprehensive, scholarly examination of quercetin, presenting a balanced view of its benefits and limitations while encouraging further research and development in medicinal chemistry and phytotherapy. It serves as an essential resource for researchers, healthcare professionals, and academicians interested in the intersection of plant-based compounds and health enhancement.

2. Section 1: Quercetin chemistry

2.1 Chemical structure and properties of quercetin

Flavonoids are a group of naturally occurring polyphenolic secondary metabolites that are broadly disseminated in the plant kingdom, particularly in fruits, grains, and vegetables. Flavonoids are also found in the form of aglycones or glycosides. Based on the diversity in their basic structure (C6-C3-C6) regarding the number and location of the hydroxyl groups and the oxidation level of the C-ring, flavonoids could be divided into seven sub-classes namely: flavonols, flavones, isoflavones, anthocyanidins, flavanones, flavanols, and chalcones (Figure 1) [9, 10].

Figure 1.

Chemical classification of flavonoids.

Quercetin (3,5,7,3′,4′-pentahydroxyflavone) is a flavonol-type structure, with its IUPAC name verified as [2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one] (Figure 1). The catechol-type B ring is mainly responsible for most biological activities of the compound; among them are antioxidants [11, 12].

Basically, quercetin occurs in the form of glycosides as well as ethers, sulfates, acyls, and prenyls. The hydroxylation pattern of quercetin (five hydroxy groups) is related to the number of derivatives as well as the biological activities of the compound [13]. Noteworthy, a common location for the glycosylation site is the hydroxyl group at the C-3 position followed by the C-7 position. Quercetin 3-O-glycosides exist as mono and/or di-glycosides, and the most common sugar moieties are glucose, galactose, rhamnose, xylose, and glucuronic acid. Quercetin 3-O-glycosides include quercetin 3-O-glucoside, quercetin 3-O-xyloside, quercetin 3-O-rhamnoside, quercetin 3-O-glucuronide, and quercetin 3-O-galactoside as mono-glycosides. In the same context, C-glycosides are likely to occur at the C-6 position [14].

Quercetin is a yellow crystalline solid with a melting point of 316°C and density equal to 1.80 g/cm³. Moreover, it has a high degree of solubility in organic solvents such as dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), methanol (MeOH), and ethanol (EtOH). On the contrary, it is difficult to absorb quercetin in the body as a hydrophobic compound due to its weak water solubility. The water solubility increases according to the increasing number of sugar moieties in the molecule. Therefore, scientists have turned to conducting many studies in order to improve its water solubility and bioavailability, which reflects positively on its pharmacological properties. Metal chelation is considered one of the methods used to improve its water solubility and bioavailability. However, the most common quercetin-metal complexes are copper and iron complexes [15, 16, 17].

2.2 Biosynthesis and natural sources

Plants are exposed to some damages from the surrounding environment, such as UV-radiation and microbial infection, so the process of flavonoids biosynthesis is considered the first line of defense against these external damages [18]. Flavonoids can be biosynthesized via the phenylpropanoid metabolic pathway. This pathway includes a group of enzymes like synthase, isomerases, hydroxylases, and reductases [19]. The biosynthesis of quercetin involves several steps and some enzyme complexes. Firstly, L-Tyrosine or 4-hydroxyphenylalanine is transformed to p-coumaric acid via using tyrosine ammonia lyase (TAL), and then p-coumaric acid is transformed into p-coumaroyl-CoA using 4-coumaroyl-CoA ligase (4CL). Subsequently, p-coumaroyl-CoA reacts with three particles of malonyl-CoA via using chalcone synthase (CHS) which resulted in the development of naringenin chalcone. After that, naringenin chalcone is transformed to naringenin using chalconeisomerase (CHI). Afterward, via using flavanone 3-hydroxylase (F3H) enzyme naringenin is transformed to dihydrokaempferol. Then, dihydrokaempferol is transformed to dihydroquercetin by using flavanone 3′-hydroxylase (F3’H) enzyme. Finally, dihydroquercetin is transformed into quercetin by using flavonol synthase (FLS) enzyme (Figure 2) [20].

Figure 2.

Biosynthesis pathway of quercetin.

Quercetin is the most abundant flavonoid, found in fruits, vegetables, and grains. The compound is widely found in many plant species such as apples, honey, raspberries, onions, red grapes, radish, cherries, pears, tomatoes, coriander, green tea, red lettuce, fennel, green beans, asparagus, green pepper, sweet potato, citrus, and dill (Figure 3) [18, 21, 22]. As a result of the diversity of the environmental conditions and Ayurvedic culture, the sources of quercetin also vary in different regions around the world [22].

Figure 3.

Some natural sources of quercetin.

2.3 Methods of extraction and purification

Previous studies indicated that quercetin has been extracted from plant materials using several extraction approaches, such as conventional solvent extraction, ultrasound-assisted extraction (UAE), supercritical fluid extraction (SFE), and microwave-assisted extraction (MAE) [23, 24, 25, 26]. Moreover, aqueous mixtures are among the best solvents used in extracting quercetin from plant materials in an effective way with sufficient extraction yield, including methanol, ethanol, acetone, and ethyl acetate [27]. For instance, in a previous study quercetin was extracted from dry onion peels with a high extraction yield (21%) using hot aqueous mixture of ethanol (60% ethanol) [28]. Quercetin has been isolated from Huberantha senjiana leaf ethyl acetate extract obtained by successive extraction and purified using conventional column chromatography packed with silica gel [29]. In another study, column chromatography and HPLC-UV were applied for the isolation and purification of quercetin from Rubus fruticosus fruit ethyl acetate extract [30]. Sambandam et al. (2016) extracted and isolated quercetin from Trigonella foenum-graecum leaf ethanol extract using maceration and column chromatography, respectively [31]. Also, quercetin has been extracted from Psidium guajava leaf using maceration by sonication in methanol: water (85:15) as the eluting solvent [32]. From the methanolic extract of Ginkgo biloba, quercetin has been extracted using solid-phase extraction (SPE) [33]. Pan and Lü reported the extraction and isolation of quercetin from Gynostemma pentaphyllum methanol extract using heat-reflux and high-speed countercurrent chromatography (HSCCC) methods, respectively [34]. Zhang et al. (2014) reported the extraction and isolation of quercetin from Zanthoxylum bungeanum 95% ethanol extract using maceration and column chromatography, respectively [35]. Additionally, quercetin has been extracted from Dendrobium officinale using the ultrasonic-assisted extraction (UAE) technique [36]. Pilařová et al. reported the extraction of quercetin from A. praecox extract using the carbon dioxide expanded liquid method [37].

3. Section 2: health benefits of quercetin

Quercetin has received great attention from scientists and researchers in the field of medicinal chemistry due to its vital therapeutic benefits and pharmacological properties. Many previous reports indicated the powerful ability of quercetin to treat many health disorders such as inflammations, oxidative stress, diabetes, viral, and microbial infections [38]. It has shown several biological properties such as antioxidant, antiarthritic, anti-inflammatory, anti-SARS-CoV-2, antiaging, antimicrobial, anti-obesity, cardiovascular, hepatoprotective, neuroprotective, anti-allergic, wound-healing, antiviral, anti-Alzheimer’s, anti-diabetic, and anticancer activities (Figure 4) [39, 40]. Herein, some pharmacological activities of quercetin are mentioned in depth.

Figure 4.

Some pharmacological activities of quercetin.

3.1 Antioxidant properties and mechanisms

Quercetin is known for its powerful antioxidant activity due to its ability to remove free radicals and protect cells from the accumulation of such serious species inside the body. It also has the ability to diminish the harmful effects resulting from the phenomenon of oxidative stress as a result of continuous exposure to some chemicals and pollutants. In addition to its potent free radical scavenging properties, quercetin has the ability to chelate with some metal ions such as Cu²⁺, Mn²⁺, and Fe²⁺ which increases its bioavailability [11, 41, 42].

Noteworthy, the structural effect of quercetin has a clear impact on its free radical scavenging activity. From the structure-activity relationship point of view, quercetin has the optimal structural requirements to achieve strong free radical scavenging activity including the presence of ortho-dihydroxy groups on the B-ring (catechol groups), unsaturated double bond between C-2 & C-3 and a carbonyl group (keto group) at C-4 on the C-ring, hydroxyl groups on the A- and C-rings at C-5 and C-3 positions, respectively, and 4-oxo group on the C-ring (Figure 5). These characteristic structural features led to stabilization of the aroxyl radical (Ar-O^•) in the B-ring via intramolecular H-bonding. Moreover, the planarity of the molecule plays a vital role in the powerful activity of quercetin as an antioxidant and free radical scavenger natural agent [43, 44, 45].

Figure 5.

Optimal structural criteria of quercetin for its effective free radical scavenging activity.

3.2 Quercetin in disease prevention and management

Numerous previous reports have demonstrated the effective role of quercetin in disease prevention and management, including cardiovascular, cancer, and diabetes diseases [5, 38, 39]. Therefore, the higher daily quercetin intake is correlated to a minimal threat of several diseases.

3.2.1 Cardiovascular health

Previous reports revealed that the intake of quercetin-rich foods led to the prevention of cardiovascular diseases. In the same context, some studies conducted on experimental animals indicate a decrease in blood pressure after receiving nutritional supplements containing quercetin, confirming the effect of quercetin as a vasodilator agent [46]. Taken together, quercetin has the ability to decrease low-density lipoprotein as well as cholesterol oxidation and to inhibit endothelial dysfunction in cardiovascular diseases [47]. Herein, Figure 6 summarized the cardioprotective effects of quercetin and its molecular mechanisms involved in cardioprotective management.

Figure 6.

The cardioprotective effects of quercetin and its molecular mechanisms.

Numerous studies showed the cardioprotective role of quercetin using experimental animal and human models. Rasheed et al. reported the cardioprotective activity of quercetin and its role in the improvement of myocardial injury resulting from high-fat diet intake in adult male albino rat model [48]. Furthermore, quercetin has the ability to relieve endothelial dysfunction in age-related cardiovascular cases based on its anti-atherosclerotic and anti-hypertensive activities [49]. In another study, quercetin supplementation at a dose of (250 mg/day) for 2 months led to the improvement of oxidative stress, blood pressure, left ventricular function, and aerobic power in men with hypertension and coronary artery diseases [50]. Additionally, quercetin could invert posttraumatic cardiac dysfunction via decreasing cardiomyocyte apoptosis across the repression of TNF-α rises, reactive species overproduction, and Ca²⁺ overburden in cardiomyocytes [51].

3.2.2 Anti-cancer properties

Quercetin is known for its chemopreventive and anti-cancer properties due to its unique chemical structure, which increases its ability to scavenge free radicals and enhance its antioxidant activity. Chemotherapy is one of the approaches used to combat cancerous diseases, in addition to surgery, radiotherapy, immunotherapy, targeted therapy, and hormone therapy. Noteworthy, quercetin has multiple mechanisms of action in treating cancer, such as cell cycle arrest, autophagy, potentiates apoptosis, drug resistance, and prevents angiogenesis and metastasis [52, 53, 54]. Quercetin has a long history in treating various types of cancer such as breast, colorectal, ovarian, blood, lung, oral, esophageal, bladder, gastric, hepatic and prostate cancers [55, 56]. The targeted cancers and the possible mechanisms of action are summarized in Figure 7.

Figure 7.

The targeted cancers and the possible mechanisms of action.

3.2.3 Diabetes and metabolic syndrome

Previous reports have shown that the daily intake of quercetin reduces most signs of metabolic syndrome, including high blood pressure, high blood sugar, insulin resistance, abdominal obesity, and abnormal cholesterol. Additionally, quercetin has the superior ability to manage type 2 diabetes and its associated dependencies [57, 58, 59]. Desai et al. reported that quercetin treatment for 8 weeks alleviates streptozotocin-induced diabetic nephropathy in rats by controlling hyperglycemia, dyslipidemia, and downregulated inflammatory activators NFκB, IL-6, and Caspase-3 [60]. In another study, quercetin treatment (70 mg/kg) alleviates diabetic encephalopathy via SIRT1/ER stress pathway in db/db mice [61]. In the same context, quercetin isolated from Edgeworthia gardneri flowers led to amelioration of type 2 diabetes mellitus by inducing insulin secretion [62]. Also, quercetin at a dose of (0.5 g/kg) led to the reduction of anxiety and decreasing hyperglycemia-related injury in induced diabetic’s rats [63]. Moreover, the administration of quercetin at a dose of (15 mg/kg, intraperitoneally) led to the reduction of fasting blood sugar and malondialdehyde levels in rats with Streptozocin-induced diabetes [64]. Additionally, Rahmani and his co-workers reported the efficacy of quercetin (50 mg/kg b.w.) to reduce diabetic complications, renal tissue damage, and renal oxidative stress in Streptozotocin-induced diabetic rats [65].

3.3 Quercetin in mental health and neuroprotection

The neuroprotective properties of quercetin are well-known versus neurotoxins, neuronal injury, and neurodegenerative diseases [66]. Recently, several studies have demonstrated the efficacy of quercetin as a possible therapeutic agent in central nervous system syndromes such anti-depressive, anti-anxiolytic, anti-neuroinflammatory, and anti-Huntington [67]. Also, quercetin has received great attention from researchers in the treatment of neurological and mental disorders, including ischemia, cognitive impairment, traumatic injury, Alzheimer’s, Parkinson’s, and Huntington’s complaints [68, 69]. Mehany et al. reported on the efficacy of quercetin in mending brain injury and cerebral alterations arising from high altitude, low pressure, and low oxygen through increasing antioxidant enzymes such as SOD, CAT, and GPx [70]. Regarding Alzheimer’s diseases, quercetin plays a vital neuroprotective role in this issue by modulating learning, memory, and cognitive tasks [69]. Quercetin also has a high ability to inhibit neuroinflammatory routes via downregulating pro-inflammatory cytokines, like NF-kB and iNOS [66].

4. Section 3: toxicity and safety profile

Quercetin is highly regarded in the scientific community for its robust antioxidant properties, which play a crucial role in mitigating oxidative stress linked to chronic diseases such as cardiovascular disorders, diabetes, and cancer [71]. As a scavenger of free radicals, quercetin effectively combats cellular damage and leverages its anti-inflammatory capabilities to mitigate chronic inflammation, often associated with various pathologies [72].

Additionally, quercetin’s anti-carcinogenic traits demonstrate its potential as both a preventative and therapeutic agent in cancer care: inhibiting cancer cell proliferation, preventing their invasion, and inducing apoptosis [73]. Yet, despite these benefits, the safety and toxicity of quercetin warrant careful consideration. While quercetin from dietary sources is safe, encapsulating the natural balance, supplementation, especially in high doses, introduces risks, including potential kidney toxicity [74, 75].

Quercetin’s interactions with bodily enzymes and drug transporters also highlight its profound biological impact but raise concerns about its ability to alter pharmaceutical metabolism, necessitating cautious use, particularly among those on medication [76].

The extensive research into quercetin’s bioactive properties, including its antioxidant, anti-inflammatory, and antiviral effects, underscores its potential as a beneficial dietary supplement. However, the principle that “the dose makes the poison” is especially relevant when assessing quercetin’s toxicity at high supplementation levels, which could pose risks such as cytotoxicity and potential mutagenicity under certain conditions [77, 78, 79, 80, 81]. This complex profile calls for a balanced approach to using quercetin, emphasizing the importance of moderation and professional guidance to harness its health benefits while avoiding adverse effects.

4.1 Toxicological insights from animal models and human clinical studies

Animal studies have been instrumental in uncovering the potential toxic effects of quercetin. Rodent models, for instance, have shown that while moderate doses of quercetin can be beneficial, excessive intake can lead to kidney and liver toxicity, highlighting the organ-specific vulnerability to quercetin’s cytotoxic effects [82]. These studies serve as a cautionary tale, suggesting that the extrapolation of quercetin’s benefits to humans requires a nuanced understanding of dose-dependent toxicity [83]. Human studies on quercetin supplementation provide valuable insights into its toxicological profile. While most clinical trials report no significant adverse effects from quercetin at moderate doses, the variability in individual metabolism and the potential for drug-nutrient interactions warrant consideration. The impact of quercetin on enzyme systems involved in drug metabolism, particularly the cytochrome P450 enzymes, poses a risk for altering the pharmacokinetics of concurrently administered medications, necessitating a cautious approach to supplementation [84].

4.2 Safe dosage and potential side effects

Quercetin, a flavonoid present in many fruits, vegetables, and grains, is celebrated for its potent antioxidant, anti-inflammatory, and anti-carcinogenic properties [73]. However, while the benefits of quercetin are substantial, careful consideration of dosage and potential side effects is crucial to maximize its therapeutic value and minimize risks [85].

Quercetin’s ability to scavenge free radicals, reduce inflammation, and regulate cell cycles contributes to its potential to mitigate chronic diseases and protecting against some cancers. Nevertheless, the principle that “the dose makes the poison” is particularly applicable here, emphasizing the importance of determining a safe dosage [86].

Research indicates that quercetin consumed through the diet is safe and contributes to lower chronic disease risks. However, supplementation, typically ranging from 500 to 1000 mg per day, exceeds dietary levels and requires careful safety evaluation [87, 88]. Health experts and regulatory bodies consider short-term supplementation of up to 1000 mg per day generally safe for most adults, but the safety of long-term use remains uncertain [89].

Potential side effects of quercetin, even if mild and transient, include headaches and tingling sensations. More seriously, high doses could impact kidney function, highlighted by animal studies suggesting possible toxicity [90, 91]. Additionally, quercetin can interact with enzymes and drug transporters, potentially altering the effectiveness or safety of other medications. This makes it crucial for those on medication to consult healthcare providers before starting quercetin supplements [92].

4.3 Interactions with pharmaceuticals and nutrients

The interaction of dietary supplements like quercetin with pharmaceuticals is crucial, particularly given quercetin’s antioxidant, anti-inflammatory, and anti-carcinogenic properties and its rising popularity as a supplement [93, 94]. This flavonoid can significantly affect the metabolism of drugs, primarily through its influence on cytochrome P450 (CYP) enzymes like CYP3A4, which metabolizes many common medications such as statins and certain antidepressants. Inhibiting CYP3A4, quercetin could increase these drugs’ plasma concentrations, raising potential toxicity risks [95, 96, 97]. Quercetin also affects drug transport mechanisms, notably P-glycoprotein (P-gp), which controls the efflux of drugs from cells. By inhibiting P-gp, quercetin might alter the efficacy and safety of drugs that are P-gp substrates, like some chemotherapeutic agents and immunosuppressants [98, 99]. Beyond pharmaceuticals, quercetin’s interactions with nutrients are significant. It can enhance the body’s antioxidative defense by synergizing with vitamins C and E, beneficial under oxidative stress conditions [100]. However, its chelating properties may affect the absorption of essential minerals like iron and zinc, which could be a concern for those with specific dietary limitations or marginal mineral status [101, 102].

Given these dynamics, integrating quercetin into therapeutic regimens demands careful consideration of both its benefits and potential risks, requiring healthcare professionals to assess individual factors and provide personalized advice to ensure safe and effective use.

5. Section 4: cutting-edge advances in quercetin research

Quercetin research within nanotechnology is promising due to its potential to enhance bioavailability and targeted delivery, overcoming traditional limitations like poor solubility and rapid metabolism [103]. Nanotechnology-based systems aim to optimize quercetin’s therapeutic use by reducing dosage and minimizing side effects [104]. Additionally, quercetin is being investigated for its synergistic effects with other treatments, particularly in cancer therapy, to improve outcomes and reduce adverse effects by modulating key biological pathways [105, 106].

Research also extends to neurodegenerative diseases, exploring quercetin’s antioxidative and anti-inflammatory properties for potential treatments for Alzheimer’s and Parkinson’s diseases [107]. In sports science, studies focus on quercetin’s role in reducing inflammation and oxidative stress, potentially enhancing athletic performance and recovery [108]. Lastly, quercetin’s impact on aging and longevity is being explored, particularly its effects on cellular mechanisms like telomerase activity and sirtuins, suggesting its use in promoting healthy aging and extending lifespan [109, 110].

5.1 Nanotechnology and quercetin delivery systems

Nanotechnology, a pluridisciplinary scientific undertaking, involves formation and utilization of materials, systems, and devices on the nanometer scale and is presently undergoing explosive development on numerous fronts [111]. Particularly in drug delivery, nanotechnology is expected to spark innovation and play a critical role in several biomedical applications [112]. Pharmaceutical industries have become progressively concerned in nanotechnological developments due to their wide benefits, for instance, targeted drug delivery, modified release systems, and the aptitude to develop novel formulations that were previously not possible [113].

Phytopharmacological and phytochemical disciplines have already established the biological abilities and composition of several herbal products [114]. The majority of the biologically active components of extracts, such as tannins, terpenoids, and flavonoids, are highly water insoluble, have large molecular sizes, and exhibit poor absorption, resulting in loss of bioavailability and efficacy [115]. Several studies have shown that herbal remedies have good activity in assays in vitro, which are not reproducible in investigations in vivo [116, 117]. Quercetin is a promising candidate for the management of various diseases. However, because of its hydrophobicity, this flavanol has a relatively low bioavailability, which must be increased to fully explore its potential [118]. Nanotechnology is an attractive option to overcome this limitation since it can enhance quercetin bioavailability at the anticipated site and, subsequently, improve therapeutic capabilities [119]. Numerous studies focus a great deal of interest on the creation of nanotechnological strategies that attempt to determine the most effective way to encapsulate and deliver quercetin for various uses (Figure 8).

Figure 8.

Illustration of quercetin-delivery nanosystems [111].

5.2 Polymers

Polymers are striking materials for the pharmaceutical industry. They result from linking many high MW monomers, forming a large chain structure [120]. Nucleic acids, pharmaceutical agents, and other bioactive substances can be transported via polymer nanoparticulate platforms, which are broadly acknowledged as novel delivery methods [121]. Micelles are colloidal nanoparticles with a nanoscale of less than 100 nm and a distinct core-shell structure, formed of a hydrophobic core and a hydrophilic outer layer [122]. Pluronic F88 and P123 were used to create quercetin-incorporated micelles. The obtained formulation by Patel et al. offered an improved bioavailability of quercetin, a slower and controlled release pattern, and better ability to hinder the growth of MCF-7 cancer cells compared to pure quercetin [123]. Qi et al. proposed a highly promising quercetin nanocarrier through the formation of polymeric micelles using Soluplus, which is an amphiphilic graft copolymer. Results obtained from in-vivo studies displayed upgraded ability of quercetin-loaded micelles to reduce tumor size and decrease adverse effects. Moreover, Soluplus–Quercetin micelles possess a multi-faceted suppressing effect on angiogenesis, making them promising systems for the targeted delivery of quercetin in cancer management [124].

Nanoparticles (NPs) can be made of a variety of biomaterials, such as polymers, lipids, etc. Polymeric nanoparticles have widely attracted the attention of the scientific community [125]. Polymeric NPs are distinguished from other particles because of their size, ranging from 10 nm to 10 μm, as well as their distinctive physicochemical characteristics [126]. Numerous bioactive substances can be accommodated into the inner part or on the outer surface of NPs [127]. pH-sensitive NPs based on Eudragit® S100 polymer were prepared by Sunoqrot et al. for the targeted delivery of quercetin to colon cancer. The results of the cytotoxic profile of quercetin incorporated into NPs on CT26 murine colon cancer cells showed a higher antitumor potency compared to the free drug [111]. Also, Huang et al. developed an impressive delivery platform for quercetin utilizing polymeric NPs comprising PEG conjugated with polyethyleneimine (PEI). The results acknowledged that quercetin polymeric PEG–PEI NPs was able to reduce inflammation and oxidative stress, and limit the renal degradation that happened by acute kidney injury [128].

5.3 Hydrogels

Hydrogels are another class of polymeric systems that may be employed as quercetin delivery systems [129]. Hydrogels are categorized into natural, synthetic, as well as hybrids based on their source. Their three-dimensional configuration is attained by the cross-linking of polymers, which allows absorption of large volumes of aqueous solutions into their polymeric network [130]. Intriguingly, Mok et al. presented a quercetin delivery system made of a methoxy poly ethylene glycol-l-poly alanine polymer to reduce pain and slow the progression of osteoarthritis. The outcomes of in-vitro release studies established the extended release of quercetin for about 1 month and the lessening of cartilage degradation attributed to osteoarthritis. The reduction was detected either with the free quercetin hydrogel or with the quercetin-loaded one; however, the presence of quercetin in the formula was found to offer further protection against the disease [131]. A polymersome is a complex configuration with a distinctive “pseudo-spherical” shell created by the self-assembly behavior of amphiphilic block copolymers. Polymersome structure is able to accommodate hydrophilic substances into the aqueous interior and to interact with the lipophilic substances on the exterior membranes [121]. Gomes et al. developed a research focused on the encapsulation of polyphenols, such as quercetin into polymersomes. Subsequently, the research results confirmed the system’s colloidal stability as well as its aptitude to be used as drug delivery system for polyphenols [132].

5.4 Lipid-based nanoparticles

Lipid-based nanoparticles (NPs), including liposomes and solid lipid nanoparticles (SLN), are increasingly used for drug delivery due to their high encapsulation efficiency and ease of surface modification [133, 134]. Liposomes, mimicking cellular membranes, consist of hydrophilic and hydrophobic phospholipids that spontaneously form bilayers in aqueous solutions, influencing their size, charge, and rigidity [135, 136]. These liposomes are particularly effective in delivering low molecular weight drugs and genes [134, 135, 136] and are biocompatible and minimally immunogenic [137, 138, 139, 140]. Studies have demonstrated liposomes’ ability to encapsulate and enhance the delivery of quercetin, a therapeutic agent, across various applications. For example, Liu et al. developed cholesterol-based liposomes for protecting against UVB-induced skin damage [141], while Shaji et al. and Yuan et al. used liposomal quercetin for liver protection and tumor suppression respectively [142, 143]. Additionally, Wong et al. utilized liposomes to deliver quercetin and vincristine to treat breast tumors [144].

For brain-related therapies, liposomal quercetin has shown potential in reducing anxiety and enhancing cognition in animal models [145, 146]. Beyond liposomes, SLN and nanostructured lipid carriers (NLC) offer benefits like physical stability and controlled drug release, though they may face issues like lipid recrystallization [147, 148, 149, 150]. Various formulations have been tested to increase quercetin’s bioavailability and efficacy, such as Li et al.’s SLN which enhanced gastrointestinal absorption [151, 152], and Dhawan et al.’s neuroprotective SLN that improved memory retention in a dementia model [153, 154].

5.5 Surfactant-based nanoparticles

Niosomes, nanovesicles made from non-ionic surfactants and lipids such as cholesterol, self-assemble into bilayers in water, encapsulating drugs effectively due to their amphiphilic nature [155, 156, 157, 158, 159, 160]. Recent studies highlight their use in delivering the antioxidant quercetin, enhancing its stability and delivery efficiency. Innovations include hyaluronic acid niosomes for anti-inflammatory effects in rats [161] and sugar esters-based niosomes for liver protection in rat models [159]. Additionally, quercetin combined with captopril in niosomes showed prolonged release and significant health benefits [162]. Nanoemulsions, colloidal dispersions of nanosized particles, demonstrate prolonged drug release and targeted cytotoxic actions in various formulations [163, 164]. A quercetin-based palm oil nanoemulsion showed potential against hepatic cancer cells [165], and other nanoemulsions improved quercetin bioavailability in diabetic rat models [166]. Inorganic nanoparticles, especially magnetic ones, are promising for targeted quercetin delivery to tumors, utilizing external magnetic fields [167, 168, 169]. Notably, Fe₃O₄ nanoparticles and SPIONs optimized with functional coatings have shown effective targeting and controlled release [170, 171]. Similarly, mesoporous silica nanoparticles (MSN), known for their stability and high drug load capacity, have shown potential in delivering quercetin for cancer therapy and skin penetration enhancement [172, 173, 174, 175]. Cyclodextrins (CDs), cyclic oligosaccharides, offer limited but effective quercetin encapsulation, potentially increasing its antioxidant effects. Specific types of CDs have shown varying degrees of effectiveness in cancer and antioxidant applications [176, 177, 178, 179, 180].

5.6 Challenges in quercetin research and application

One of the primary challenges in quercetin’s application lies in its bioavailability and solubility. Quercetin has poor water solubility, which significantly hampers its absorption and bioavailability when ingested. This limitation restricts the amount of quercetin that enters the circulation and reaches the target tissues, thereby diminishing its therapeutic effectiveness [181, 182]. Researchers are exploring various strategies, including nanoparticle delivery systems and complexation with cyclodextrins, to enhance the solubility and bioavailability of quercetin. While these approaches show promise, they also introduce additional complexity and cost to the development of quercetin-based therapies [183]. Another challenge is the lack of standardized dosing guidelines for quercetin supplementation. The optimal dose of quercetin can vary significantly depending on the condition being treated, the form of quercetin used (e.g., quercetin dihydrate vs. aglycone), and individual factors such as age, gender, and metabolic health [184]. Establishing comprehensive dosing guidelines requires extensive clinical trials across diverse populations, a process that is both time-consuming and costly. Without standardized dosing, the efficacy and safety of quercetin supplementation remain variable, complicating its clinical application [185].

Quercetin’s interactions with pharmaceuticals present a significant challenge in its application. As an inhibitor of several cytochrome P450 enzymes and a modulator of drug transporters like P-glycoprotein, quercetin can affect the metabolism and efficacy of various medications. This interaction poses risks of adverse effects or reduced therapeutic effectiveness of drugs, particularly in polypharmacy scenarios common in chronic disease management. Understanding and mitigating these interactions requires detailed pharmacokinetic studies and personalized medicine approaches, adding layers of complexity to quercetin’s clinical use [95].

The long-term safety of quercetin supplementation is yet another area that necessitates further investigation. While quercetin is generally considered safe when consumed in amounts typically found in a diet rich in fruits and vegetables, the safety of higher doses used in supplements over extended periods is less clear. Potential concerns include kidney toxicity and interactions with hormone-sensitive conditions. Longitudinal studies are crucial to assess the long-term safety of quercetin and provide clear guidance for its use [186].

5.7 Future directions in quercetin studies

A pivotal area of future research lies in addressing quercetin’s limited bioavailability. Innovative strategies such as nanotechnology-based delivery systems, liposomal encapsulation, and complexation with other molecules promise to enhance the solubility, stability, and tissue targeting of quercetin. Further development and optimization of these delivery methods are crucial to maximize quercetin’s therapeutic efficacy. Investigations into the pharmacokinetics of these novel formulations will provide valuable insights into optimizing dosage and administration routes, paving the way for more effective quercetin-based therapies [187, 188, 189].

While preclinical studies have provided substantial evidence of quercetin’s beneficial effects, there is a pressing need for comprehensive, large-scale clinical trials to validate these findings in human populations. Future research should focus on diverse demographic groups, encompassing various ages, genders, and ethnic backgrounds to ensure the generalizability of results. Clinical trials designed to investigate specific health outcomes, dosage optimizations, and long-term safety will be instrumental in establishing quercetin’s role in preventing and treating diseases, as well as in dietary recommendations and supplement formulations [85, 190, 191]. Understanding the precise mechanisms through which quercetin exerts its effects remains a significant challenge. Future studies should delve deeper into the molecular and cellular pathways modulated by quercetin, employing cutting-edge techniques such as transcriptomics, proteomics, and metabolomics. Research into the epigenetic modifications induced by quercetin could uncover novel mechanisms of action and potential therapeutic targets. This mechanistic insight will not only advance our understanding of quercetin’s biological activities but also facilitate the identification of synergistic interactions with other compounds and drugs [192, 193, 194, 195]. Given the rising prevalence of chronic diseases worldwide, quercetin’s potential role in management and prevention strategies warrants further exploration. Future research should aim to elucidate the efficacy of quercetin supplementation in chronic disease conditions such as cardiovascular diseases, diabetes, neurodegenerative disorders, and various forms of cancer. Studies evaluating the impact of quercetin on disease progression, quality of life, and survival outcomes will be particularly valuable. Additionally, exploring the preventive aspects of quercetin in at-risk populations could lead to novel strategies for disease prevention and health promotion [196, 197]. The field of personalized medicine offers exciting possibilities for tailoring quercetin-based interventions to individual genetic profiles and health conditions. Future directions in quercetin research should include investigations into the interplay between genetic variations, quercetin metabolism, and therapeutic outcomes. This personalized approach could optimize the benefits of quercetin supplementation, minimize potential adverse effects, and identify populations that may derive the most significant benefits from quercetin interventions [105, 198].

Lastly, research into the environmental and agricultural factors affecting quercetin content in foods could enhance our understanding of how to maximize dietary quercetin intake through food sources. Studies on the effects of soil quality, climate change, and farming practices on the quercetin concentrations in crops could inform agricultural guidelines and dietary recommendations, promoting optimal health through natural dietary sources of quercetin [199].

5.8 Ethical and regulatory considerations

As quercetin—a naturally occurring flavonoid known for its antioxidant and anti-inflammatory properties—gains popularity, it is crucial to address the ethical and regulatory aspects that shape its research and usage [200]. This focus is driven by its increasing application in health-related products and the need for rigorous oversight to ensure public safety and scientific integrity [201].

Ethically conducting quercetin research involves safeguarding participant welfare and rights in clinical trials. This includes adhering to ethical standards like informed consent, privacy, and equitable participant selection. Itis essential to communicate the risks and benefits transparently and to ensure that research findings are reported accurately, without overstating quercetin’s effects or underreporting its potential risks [202, 203].

Regulatory oversight is vital for turning quercetin research into safe and effective treatments. Unlike pharmaceuticals, dietary supplements containing quercetin might not undergo stringent testing, leading to variability in product quality. Regulatory bodies need to enforce strict standards for manufacturing, labeling and claims substantiation to guarantee that health claims are scientifically backed and conveyed accurately [204, 205, 206]. Additionally, the marketing of quercetin supplements should responsibly reflect the scientific evidence to avoid misleading consumers. Regulators and ethical bodies must ensure that promotional materials are truthful, helping consumers make informed decisions and preventing undue reliance on supplements for serious health issues. Strict guidelines and enforcement are essential to balance promoting quercetin’s health benefits with protecting public and consumer interests [207, 208].

6. Conclusion

Quercetin, with its robust presence in the plant kingdom, serves as a cornerstone of the flavonoid family, offering a diverse array of health benefits owing to its potent antioxidant, anti-inflammatory, and anti-carcinogenic properties. Its molecular architecture enables a multitude of pharmacological activities, making it a beacon of hope against chronic diseases such as cardiovascular ailments, diabetes, and various forms of cancer. The historical and contemporary interest in quercetin underscores its significance not only as a nutritional component but also as a potential therapeutic agent, drawing attention to its integration into pharmaceutical formulations, cosmetics, and food production. However, the leap from dietary component to therapeutic agent is bridled with challenges, notably concerning bioavailability, toxicity, and interaction with pharmaceuticals. Quercetin’s poor solubility and rapid metabolism have spurred research into innovative delivery systems, including nanotechnology-based solutions, which promise to enhance its bioavailability and therapeutic efficacy. Yet, these advances bring forth regulatory and ethical considerations, especially regarding dosage standardization and long-term safety. The potential adverse effects and toxicity associated with high doses of quercetin or its interaction with drugs underscore the necessity of a prudent approach to supplementation. Ethical and regulatory frameworks must evolve in tandem with scientific advancements to ensure quercetin’s safe and effective application. The exploration of quercetin’s interactions with pharmaceuticals and nutrients further highlights the complexity of its integration into therapeutic regimens, necessitating personalized medicine approaches to optimize its benefits while minimizing risks. Cutting-edge research into nanotechnology and targeted delivery systems opens new vistas for quercetin’s application, promising to overcome the barriers of bioavailability and offering new strategies for disease prevention and treatment. These innovations, coupled with a deeper understanding of quercetin’s mechanisms of action and its impact on chronic diseases, portend a future where quercetin could play a pivotal role in enhancing human health.

In conclusion, quercetin stands at the crossroads of tradition and innovation, embodying the promise of natural compounds in advancing human health. As research continues to unravel its complexities, a balanced approach—rooted in scientific rigor, ethical considerations, and regulatory oversight—is essential. By navigating the challenges and harnessing the advances in quercetin research, the scientific community can unlock its full potential, paving the way for novel therapeutic strategies that capitalize on the synergies between natural compounds and cutting-edge technology.

Acknowledgments

The authors acknowledge the use of QuillBot for language polishing of the manuscript.