Enhancing Polyphenol Bioavailability through Nanotechnology: Current Trends and Challenges

Abstract

Polyphenols are a class of plant secondary metabolites that have increasingly been gaining traction due to their multiple roles as therapeutics, food supplements, and preservatives. They are widely used in various foods to enhance flavor, texture, shelf life, and overall quality. Polyphenols are efficient antioxidants and radical scavengers with significant health benefits, including anti-inflammatory and antimicrobial effects. Several studies demonstrated that an increased consumption of polyphenol-rich foods may help reduce the risk metabolic disorders and cancer. However, their bioavailability is limited after ingestion due to low water solubility, instability at low pH values, and difficulties for absorption in the small intestine. To address these challenges, new technological processes and the use of nanoparticles loaded with polyphenols encapsulation and nanotechnology are required to improve polyphenol bioavailability and to maintain their biological activities, making them more effective as functional food ingredients and drug delivery systems. This chapter covers the latest trends and innovative techniques in polyphenol-based nanotechnology and explores the challenges associated with their use in these applications.

1. Introduction

Polyphenols are a class of chemical components found naturally in various plants, including vegetables, fruits, and cereals. They are characterized by complex structures, including phenolic acids, flavonoids, anthocyanins, and tannins, which can be isolated directly from natural sources or obtained through processing.

Polyphenols are antioxidants that possess anti-inflammatory and anticancer properties due to their chemical structure [1]. They have the potential to prevent chronic and degenerative diseases, including cardiovascular, cancer, liver, and neurological diseases [2, 3].

Despite their wide range of biological effects, polyphenols face degradation challenges after extraction due to factors such as pH and oxygen [4]. The variation in postconsumer circulation can be attributed to several factors, particularly the low solubility in water and sensitivity to light, heat, and environmental conditions during processing [5]. Additionally, the suboptimal bioavailability of polyphenols is influenced by various factors, including harvest conditions, food processing methods, and interactions between compounds and host factors [6]. Furthermore, the limited solubility of these compounds in body fluids and their rapid metabolism in vivo significantly impact their overall bioavailability [7]. This restricts the use of many of these compounds in nutraceuticals and as therapeutic agents. The bioavailability of polyphenols is influenced by several factors, such as molecule dimensions, degree of polymerization, the presence and type of sugar in the molecule, and their hydrophobicity.

This chapter examines the potential of novel delivery systems to enhance the bioavailability of polyphenols. Nanotechnology is a promising avenue for investigation, given the challenges posed by polyphenol’s low solubility and rapid metabolism. Nanocarriers, such as nanoparticles, liposomes, and nanoemulsions, have the capacity to encapsulate and protect polyphenols from degradation in the gastrointestinal tract, thereby improving their bioavailability.

Furthermore, nanotechnology can be employed to deliver polyphenols to specific tissues or cells, thereby enhancing therapeutic efficacy while reducing the incidence of systemic side effects.

2. General aspects of polyphenols

2.1 Classification and properties of plant polyphenols

Polyphenols represent a diverse group of phytochemicals that are abundant in fruits and vegetables. These compounds play an essential role in plant adaptation to stressors such as infection, UV exposure, or injury. They comprise over 8000 phenolic structures that are synthesized via pathways such as the pentose phosphate and shikimate phenylpropanoid structures [8, 9]. These compounds, which are characterized by the presence of one or more phenolic hydroxyl groups, represent form the primary heterogeneous group of secondary metabolites in plants [10, 11]. Polyphenols exist in free or bound forms, with free phenolics being readily soluble in water or organic solvents and bound phenolics being covalently bound to other molecules (Figure 1).

Figure 1.

Chemical structure of the main polyphenols and their biological relevance [12].

Phenolic compounds exist in conjugated form with one or more sugar molecules, forming glycosides linked by hydroxyl (OH) groups (O-glycosides) or carbon-carbon bonds (C-glycosides). These sugar linkages can be monosaccharides, disaccharides, or even oligosaccharides, with glucose being the most common. However, it can also bind to galactose, rhamnose, arabinose, xylose, or glucuronic acid [13].

The concentration and nature of polyphenols in plant foods vary depending on a number of factors, including plant genetics, growing conditions, soil composition, harvest maturity, and postharvest handling [14]. These compounds, which include phenolic acids, flavonoids, stilbenes, and lignans, have different chemical structures and can be broadly categorized as flavonoids and non-flavonoids [15].

Flavonoids, which are found in a wide variety of plant foods, play an important role in plant growth, development, flowering, fruiting, and the vibrant colors of fruit and vegetables. They form a central category of polyphenols, sharing a common diphenylpropane structure (C6-C3-C6). This group is further subdivided into eight primary subclasses, defined by variations in the heterocyclic ring. These subclasses include flavonols, flavones, flavanones, isoflavones, flavanols, anthocyanins, proanthocyanidins, and tannins [16]. Quercetin and kaempferol, well-known members of the flavonol group, are often found in glycosylated forms, which increases their solubility and stability.

Anthocyanins are water-soluble pigments that impart blue, purple, and red hues characteristic of fruits and vegetables. These pigmented compounds are glycosides of anthocyanidins, a structural class that renders them unstable in their native form. However, attachment of glucose molecules stabilizes them.

Non-flavonoids are composed of one or two aromatic rings and are classified as phenolic acids, which contain a C6-C1 carbon skeleton, hydroxycinnamates with a structure of C6-C3, hydrolysable tannins with one or two aromatic rings, and stilbenes, with a more complex structure of C6-C2-C6 [17, 18].

Phenolic acids are the most abundant non-flavonoid polyphenols, and they are found in a wide range of plant foods, such as coffee, tea, and fruits. These compounds possess diverse carbon backbones and hydroxyl group arrangements. Hydroxybenzoic acids are derived from benzoic acid, while hydroxycinnamic acids such as caffeic acid and ferulic acid contribute to the phenolic acid category. These compounds play a multifunctional role in foods, assisting in the retention of color, the inhibition of microbial growth, and the prevention of lipid oxidation, thereby extending the shelf life of foods [19].

Stilbenes are characterized by the presence of a 1,2-diphenylethylene nucleus with hydroxyl substituted on the aromatic rings and exist in the form of monomers or oligomers [20]. The main compound representative of stilbenes is resveratrol, which is primarily concentrated in grapes, berries, and peanuts. Resverastrol has been demonstrated to exert immune-boosting, anti-inflammatory, and anti-angiogenic effects.

2.2 Beneficial effects of polyphenols

Plant polyphenols offer a wide range of health benefits to humans. Their remarkable biological activities, including antioxidant and antibacterial properties, combined with their natural availability and compatibility with the human body, make them valuable additions to foods, giving them unique functional properties that promote human health. As antioxidants, polyphenols play a crucial role in the prevention of various diseases by neutralizing free radicals and protecting DNA from oxidative damage [21]. A study by Grzesik et al. [22] demonstrated that the antioxidant capacities of catechins were found to be particularly noteworthy, exhibiting superior efficacy in scavenging ABTS radicals and protecting against oxidative damage. These properties position polyphenols such as catechins as promising candidates for antioxidant therapy and prophylaxis. Similar effects were observed with a grape seed extract rich in catechins, proanthocyanidins, and anthocyanidins in the human keratinocyte cell line HaCaT. The antioxidant activity of the extract shielded keratinocytes from ROS formation; mitigated oxidative stress, DNA damage, and apoptosis; and increased cell survival [23].

Polyphenols have been found to have significant anticancer properties by inhibiting tumor growth and inducing apoptosis in malignant cells. Flavonoids regulate the activity of ROS-scavenging enzymes, participate in cell cycle arrest, induce apoptosis and autophagy, and suppress cancer cell proliferation and invasion [24]. A study conducted by Lee et al. [25] highlights the important roles of compounds such as resveratrol and quercetin in impeding cancer progression through various mechanisms, including apoptosis and antioxidant capabilities. Furthermore, silymarin has been demonstrated to induce apoptosis in liver cancer cells, indicating promising preventive and therapeutic effects against liver diseases. Similarly, epigallocatechin gallate (EGCG) and curcumin have demonstrated significant anticancer effects on breast cancer [26, 27]. Additionally, research has shown that phenolic acid can inhibit the activation of the tumor protein p53, which can enhance the effectiveness of conventional chemotherapy [28, 29].

Resveratrol, a stilbenoid polyphenol found in whole grains, exerts a neuroprotective effect in 6-hydroxydopamine (6-OHDA)-induced Parkinson’s disease by reducing DNA condensation and vacuolization of dopaminergic neurons in the substantia nigra, as shown in the study by Bhullar and Rupasinghe [30]. In a noteworthy clinical trial, daily consumption of anthocyanin-rich cherry juice showed significant benefits in older adults with Alzheimer’s disease. Improvements were observed in verbal fluency, short-term memory, long-term memory, and a reduction in both systolic and diastolic blood pressures [31].

Other beneficial effects have been attributed to various polyphenols. Ding et al. [32] have demonstrated the anti-inflammatory potential of hesperidin, highlighting its effectiveness in reducing nitric oxide (NO), interleukin (IL-6), and tumor necrosis factor (TNF-α) levels both in vitro and in vivo. These findings underscore the valuable anti-inflammatory properties of certain polyphenols.

Phenolic compounds can modulate lipid metabolism, inhibit low-density lipoprotein (LDL) oxidation, increase high-density lipoprotein (HDL) levels, induce vasodilation, and reduce the risk of coronary diseases, ischemia, and cardiomyopathies. They also inhibit platelet aggregation, enhance endothelial function, and decrease the expression of cell adhesion molecules [33].

Phenolic acids have been identified as having a multitude of beneficial effects on human health, including anti-inflammatory, anti-allergenic, antidiabetic, immunoregulatory, and cardioprotective properties [34]. Studies have demonstrated that plant-derived phenolic acids possess tyrosinase-inhibiting activity, which can be exploited to treat UV light-induced skin hyperpigmentation [35, 36, 37, 38, 39].

3. Bioavailability of polyphenols

Polyphenols have gained significant attention due to their potential health benefits. However, the bioavailability of polyphenols is limited due to their low solubility and uptake in the gastrointestinal tract. Additionally, polyphenols are susceptible to degradation in light, heat, and alkaline environments due to their numerous -OH groups [40]. Studies have shown that only a small fraction of dietary polyphenols can be absorbed and reach their target cells to exert their biological effects. To fully exploit the potential health benefits of polyphenols, it is crucial to comprehend their bioavailability.

Bioavailability, in conjunction with the polyphenol content in foods and their distribution in plants, represents a pivotal factor that directly influences and determines the biological function of consuming polyphenol-rich foods. It is crucial to distinguish between bioaccessibility and bioavailability.

Bioaccessibility is defined as the proportion of a food substance that reaches the gastrointestinal tract, where it is subjected to digestion, absorption by intestinal epithelial cells, and undergoes metabolic transformations in the intestine and liver [41]. In general, bioaccessible phenolic compounds make up less than 30% of the total phenolic content in vegetables, fruits, and nuts before digestion. In some cases, the bioaccessibility can reach up to 50% of the total polyphenol content [42]. In contrast, bioavailability refers to the release of a bioactive compound from the food matrix, its subsequent digestion, absorption, metabolism in the liver and intestine, and distribution to target tissues or storage in human cells, cultures, or organs where it exerts its bioactivity [43]. Therefore, any condition that affects the bioaccessibility of a bioactive compound directly affects its bioavailability.

The bioavailability, absorption, and metabolism of polyphenols are profoundly influenced by the chemical structure of the compounds and the diversity of species and genera of the gut microbiota. In addition to intestinal factors, the biochemical transformations of polyphenols and the types and proportions of their derivative metabolites depend on systemic host factors such as sex, age, presence of pathologies, and genetics [44].

During gastric digestion, most phenolic compounds resist acidic conditions [45]. Biotransformation processes, such as deglycosylation, also play a critical role in determining bioavailability. Many polyphenols (aglycones) are hydrophilic and can diffuse across biological membranes for absorption, while glycosylated polyphenols (glycons) require hydrolysis of linked sugar groups by intestinal enzymes or colonic microflora prior to absorption [46, 47].

The bioavailability of polyphenols is intricately linked to the different pH levels and enzymatic activities present in the gastrointestinal fluids (GIF) along the digestive tract. The acidic environment of the stomach (pH 1.2) and the more neutral conditions of the small intestine (pH 6.8), along with various gastrointestinal tract (GIT) metabolizing enzymes, exert a significant influence on the fate of orally administered polyphenols. Consequently, numerous polyphenols are susceptible to degradation in the acidic environment of the stomach and enzymatic breakdown in the gastrointestinal tract, resulting in reduced bioavailability [48]. Intestinal absorption of polyphenols is strongly influenced by their chemical structure and the nature of the sugars in their glycosylated form [49]. Typically, polyphenols are glycosylated and the attached sugars are usually released prior to absorption. Several dietary compounds, including dietary fiber, lipids, proteins, and digestible carbohydrates, can modulate the availability of polyphenols for absorption after ingestion. Furthermore, the ability of polyphenols to bind to proteins represents a significant limitation to their absorption.

During digestion, complex polyphenols are broken down into simpler molecules by several enzymes. Insoluble complexes, such as those composed of phenolic moieties and indigestible polysaccharides [50], protein [51], and other dense polyphenols, including condensed tannins and lignins [52], are also present. The bioavailability of polyphenols varies. Isoflavones have the highest bioavailability, followed by phenolic acids, flavanols, flavanones, flavonols, anthocyanins, and proanthocyanidins [53]. The absorption of hydrophobic compounds such as curcumin and naringenin is low due to rapid metabolism and excretion [54]. Anthocyanins are known to be unstable, particularly during food processing and exposure to gastrointestinal diseases, which can limit their absorption [53].

Polyphenols that are not absorbed in the small intestine are transferred to the colon, where they are converted by the colonic microflora into other bioactive phenolic metabolites. These metabolites undergo structural modifications, mainly in the liver, before entering the bloodstream [55, 56, 57, 58].

Although initially considered indigestible due to their linkage to sugars, flavonoids undergo hydrolysis, allowing aglycone portion to penetrate the intestinal epithelial cells. After ingestion, flavonoid metabolites appear in the plasma after being processed by phase II enzymes in the liver and small intestine. However, the hydrophilic nature of glycosylated flavonoids limits their passive diffusion across the small intestine, resulting in minimal absorption. The instability of tea flavonoids in the colon may contribute to their poor bioavailability and absorption [59].

4. Approaches for enhancing the bioavailability of polyphenols

To address the challenge of limited bioavailability of polyphenols, nanotechnology, in particular nano-based carriers, has emerged as a promising avenue for enhancing the absorption of polyphenols. The minute size of nanoparticles allows them to traverse small capillaries and cells, facilitating maximal polyphenol accumulation and sustained release [60]. Investigations are being conducted into the use of lipid-based materials, dendrimers, and polymeric nanoparticles. Polymeric nanoparticles are favored due to their properties such as biodegradability and surface modifiability (Figure 2) [61].

Figure 2.

Different type of nanocarriers used for polyphenols delivery.

Polyphenols can be protected by various nanocarriers, including polymeric nanoparticles, micelles, cyclodextrins, and gelatin [62]. Protein-based nanoparticles and chitosan are promising options for polyphenol nanocarriers [63].

A variety of nanoparticles have been employed to encapsulate and enhance the bioavailability of hydrophobic polyphenols. These include both organic and inorganic variants. Organic nanoparticles are derived from proteins, carbohydrates, and protein-polysaccharide complexes, while inorganic nanoparticles are primarily composed of gold, silver, and silica [64]. Polyphenols, including curcumin, rutin, and catechin, can be encapsulated using techniques such as nanoencapsulation and ionic gelation to enhance their bioavailability and stability [65, 66]. Studies on liposomal encapsulation and nanoencapsulation have highlighted the beneficial effects of polyphenols [67]. Nanoencapsulation has been shown to be a promising method for delivering various hydrophobic polyphenols in vivo [68].

There are a number of nanoscale delivery methods for polyphenols, including biopolymer-based nanoencapsulation, natural nanocarriers, and specialized device-based techniques. The use of nanoscale materials and structures allows researchers to overcome the barriers of absorption, distribution, metabolism, and excretion that often limit the bioavailability of compounds.

4.1 Nanoencapsulation

The use of nanotechnology to improve the bioavailability of polyphenols is an important area of research in the field of bioactive compounds. Nanoencapsulation, a leading technique in nanotechnology, is gaining popularity for its ability to enhance the protection and absorption of phenolics. By reducing particle size to the nanoscale, nanoencapsulation increases the surface-to-volume ratio, which improves bioavailability [69]. For instance, gelatin nanoparticles act as protective barriers for core polyphenols, such as resveratrol, shielding them from the harsh gastric environment and aiding in their transportation to the intestinal sites for efficient absorption [70]. Encapsulation systems, such as bovine serum albumin, can function as controlled release mechanisms, increasing the bioavailability of polyphenols like rutin while reducing their excretion rates [70]. The encapsulation of epigallocatechin gallate (EGCG) into chitosan nanoparticles (CSNPs) has been demonstrated to significantly inhibit the proliferation of human melanoma cells in both laboratory and animal studies [71]. Chitosan (CS), which is derived from crustacean shells, is commonly used in biomedicine due to its exceptional physicochemical and biological properties [72]. Additionally, CSNPs enhance the exposure of green tea extract to plasma by improving intestinal stability [73]. Consequently, nanoencapsulation represents a promising system for the efficient transport and release of phenolic compounds to target tissues. The encapsulation approach offers numerous benefits for enhancing the bioavailability of various polyphenols.

4.2 Lipid nanoparticles

Lipid nanoparticles (solid lipid nanoparticles, SLNs, and nanostructured lipids carriers, NLCs) are nano-sized (100–400 nm) colloidal lipid particles consisting of solid and surfactants with or without lipids. SLN and NLC were selected due to their numerous advantages, including high loading capacity, increased stability, controlled drug release, enhanced bioavailability, and biocompatibility for delivering natural compounds to the brain [74, 75].

The morphological structure of SLNs and NLCs resembles that of a lipid bilayer in a membrane, with surfactants on the outside and lipids in the center of the matrix. Based on its structure, NLCs can encapsulate both hydrophobic and hydrophilic drugs internally and externally, respectively. SLNs have the potential to improve the bioavailability of antioxidant nutraceuticals by increasing their solubility and permeability [76, 77].

The utilization of SLN and NLC in oral administration notably improved the bioavailability of curcumin extract [78]. In vivo studies demonstrated that SLNs loaded with resveratrol achieved a higher maximum plasma concentration compared to the physical mixture. Similarly, SLNs loaded with epigallocatechin gallate (EGCG) exhibited significantly higher maximum plasma concentration levels compared to free-form EGCG. Additionally, NLCs exhibited an initial burst release followed by a controlled release, ultimately leading to enhanced drug release and absorption, resulting in efficacious therapeutic outcomes [78].

4.3 Nanoliposome

Liposomes, small vesicles consisting of a bilipid layer enclosing an aqueous core, allow the encapsulation of both hydrophilic and lipophilic materials [79]. This encapsulation mechanism protects molecules from degradation and systemic dilution. Nanoliposomes not only encapsulate hydrophilic and hydrophobic substances, enhancing the solubility and utilization of polyphenols, but also control the release rate of these components, ensuring stability and efficacy [80]. In comparison with other nano-delivery systems, nanoliposomes have advantages such as ease of degradation, reduced immunity, reduced toxicity, and enhanced activity.

The encapsulation of epigallocatechin gallate (EGCG) in nanoliposomes, which are known for their stability under acidic conditions, followed by combination with alginate and chitosan particles, demonstrated high encapsulation efficiency (>97%) and a slow-release effect, effectively mitigating EGCG degradation [81]. This interaction enhances the bioaccessibility and/or bioavailability of polyphenols, exemplified by EGCG’s ability to interact with lipid molecules, particularly in the lipid ester region. This results in the formation of stable and organized liposomes that prevent aggregation at higher catechin concentrations. As demonstrated by Tonnesen et al. [82], the incorporation of curcumin into liposomes resulted in a 20-fold increase in curcumin concentration in red blood cells when compared to the dilution of curcumin in Dimethylsulfoxide (DMSO). The improved solubility of quercetin in liposomes led to an increase in bioactivity, which was attributed to longer exposure of the cells to the active substance [83].

4.4 Phytosomes

Phytosomes are complexes of lipid molecules formed by binding plant extracts or their components to phospholipids, primarily phosphatidylcholines [84]. These complexes have been demonstrated to enhance bioavailability by providing an environment with increased lipophilicity. For instance, in vitro dissolution studies have shown that catechin-phospholipid complexes exhibit sustained release over 24 hours and superior antioxidant activity compared to free catechins at all tested doses [85]. Furthermore, the naringenin-phospholipid complex exhibited superior drug content and improved drug release in comparison with free naringenin during the in vitro dissolution studies conducted in distilled water [86].

4.5 Dendrimers

Dendrimers are branched polymer structures that have been extensively researched as effective drug carriers. Scientists are currently exploring new dendrimer-based formulations with the requisite properties for biomedical applications, including enhanced bioavailability, low toxicity, and high transfection profiles [87]. In order to combine the medical properties of caffeic acid with the drug delivery properties of dendrimers, a new class of polyphenolic dendrimers has been synthesized [88]. Grodzicka et al. [87] have synthesized carbosilane dendritic systems containing one or two caffeic acid units and ammonium groups on the surface to render them water-soluble. Their findings indicate that conjugation of polyphenols with cationic carbosilane dendrimers could be a promising approach to enhance the bioavailability of these powerful antioxidants.

To optimize the flavonoids bioavailability, Vergara-Jaque et al. [89] nanoencapsulated synthetic and natural variants, including quercetin, using G5-PAMAM dendrimers under both neutral and acidic conditions. The study revealed that the entrapment process was notably faster under acidic conditions than under neutral pH levels.

4.6 Polymeric micelles

Polymeric micelles, with a diameter ranging from 20 to 100 nm, are composed of amphiphilic polymer molecules. The use of polymeric micelles can help avoid unwanted effects [90]. The hydrophobic core of these micelles can encapsulate water-insoluble substances, while the hydrophilic corona protects the core, preventing removal by the reticuloendothelial system (RES), prolonging circulation time, and enabling interaction with blood components. Micelles have been observed to migrate from tumor vessel walls to cancer cells [91], as evidenced by the finding of Huan Li et al. [92], who conducted an in vitro gastrointestinal release test on micelles of curcumin and quercetin co-loaded. The test demonstrated that micelles exhibited pH-dependent release, releasing a small amount of polyphenol in simulated gastric fluid but presenting sustained release in the simulated intestinal fluid. The gastrointestinal-digested polyphenol-loaded micelles exhibited excellent antioxidant ability.

4.7 Nanogels

Nanogels are effective nanocarriers for delivering food-grade active substances to the gastrointestinal tract. This facilitates their conversion into particles that are crucial for the digestion and absorption processes [92, 93]. Jin et al. [94] developed a nanogel using soy protein and dextran self-assembly to deliver riboflavin effectively. Nanogels composed of carboxymethyl starch and chitosan hydrochloride, formed through chemical cross-linking, are effective carriers for bioactive compounds such as curcumin [95].

The self-assembly of natural proteins and polysaccharides into nanogels has garnered attention for their potential to deliver bioactive molecules. In this study, carboxymethyl starch-lysozyme nanogels (CMS-Ly NGs), synthesized through eco-friendly electrostatic self-assembly, were utilized to deliver epigallocatechin gallate (EGCG). The nanogels achieved an EGCG encapsulation rate of 80.0 ± 1.4% and maintained a stable particle size. Under simulated gastrointestinal conditions, CMS-Ly NGs with EGCG exhibited controlled release, which enhanced bioavailability. Furthermore, CMS-Ly NGs were able to encapsulate anthocyanins and demonstrated slow-release properties during gastrointestinal digestion. These findings demonstrate the potential of protein and polysaccharide-based nanogels for delivery of bioactive compounds [96].

4.8 Inorganic nanoparticles

Due to their controllable size and shape, as well as their great specific surface area, inorganic nanoparticles have gained attention in enhancing the bioavailability of polyphenolic compounds. Gold and silver nanoparticles are the most widely used nanocarriers to enhance the bioavailability of polyphenols [97]. In addition, silica, titanium dioxide, and magnetic iron oxide nanoparticles have also been used in drug-delivery systems [98, 99, 100].

Several studies have shown that silver and gold nanoparticles have the potential to serve as nanocarriers to improve the bioavailability of curcumin [98, 101]. Additionally, research has demonstrated that EGCG-gold nanoparticles have greater anticancer efficacy than free EGCG and EGCG-gold nanoparticles synthesized through the citrate method [90]. Gold nanoparticles are excellent nanocarriers for tracking the absorption of polyphenols through imaging techniques due to their small size.

5. Nanotechnology challenges

Nanopolyphenols present several challenges regarding their biological properties, biocompatibility, and safety. In the field of nanomedicine, these challenges include limited understanding of nanomaterial interactions with tissues and cells, as well as uncertainties regarding their biological interactions within the body. Additionally, there is a need for specialized toxicological studies for nanopolyphenols and ensuring structural stability post in vivo administration. It is also important to address the accumulation of nanoparticles in target organs, tissues, and cells. These challenges have been previously highlighted studies [102]. Additionally, the high cost of raw materials required for nanopolyphenols synthesis presents challenges for scalability and manufacturing. To justify these expenses, nanomedicine products must exhibit significantly improved clinical therapeutic effects compared to conventional therapies [103].

Despite these challenges, the use of nanotechnology in designing and formulating nanomedicines derived from polyphenols is expanding in both nutraceutical and pharmaceutical markets. Nevertheless, comprehensive nanotoxicity studies remain insufficient, despite clinical trials indicating only mild adverse effects resulting from nano-polyphenol administration [104]. To address potential nanotoxicity challenges, it is necessary to have adequate screening platforms that can predict the toxicological behaviors of nano-formulated products. This will enable the implementation of safety parameters that meet international standards [105].

6. Conclusion and future perspectives

Despite the numerous challenges associated with polyphenol bioavailability, such as low solubility, susceptibility to degradation, and limited absorption, nanotechnology offers a promising approach and innovative solution to overcome these obstacles. Techniques such as nanoencapsulation, lipid nanoparticles, nanoliposomes, phytosomes, dendrimers, polymeric micelles, and nanogels protect polyphenols from degradation in the gastrointestinal tract, enhance their transport to target sites, and improve their absorption and therapeutic efficacy.

However, the field of nanopolyphenols also presents several challenges that need to be addressed. These challenges include understanding the biological properties and interactions of nanomaterials, ensuring biocompatibility and safety, addressing potential nanotoxicity, and optimizing manufacturing processes to reduce costs and scale up production. However, comprehensive toxicological studies are needed to assess the potential risks associated with nanopolyphenols in order to fully exploit the therapeutic potential of polyphenols.

Overall, the integration of nanotechnology with polyphenol delivery systems holds great promise for revolutionizing the use of polyphenols in functional foods, nutraceuticals and pharmaceuticals. Continued research and development in this area is critical to unlocking the full potential of polyphenols in promoting human health and combating various diseases.

Conflict of interest

The authors declare no conflict of interest.