Unlocking the opportunities and challenges of green strategies for bioavailability enhancement of polyphenols

1 Introduction

Bio-sustainability has been a major paradigm shift in modern pharmaceutical and nutraceutical sciences. Typical extraction and encapsulation methods often require high energy and synthetic excipients and often use hazardous organic solvents; it is estimated that 80%–90% of pharmaceutical process waste comes from organic solvents alone, which have extremely high environmental impact factors (E-factors) (Richardson et al., 2025). This has been a concern for many regarding hidden toxicity, the environment, and long-term translational applicability. Furthermore, environmental contamination from pharmaceutical residues and the generation of solvent-associated waste during pharmaceutical formulation have heightened the importance of alternative, safer, and more environmentally friendly formulation processes (United Nations Environment Programme, 2024). Among naturally occurring bioactive compounds, polyphenols are the most widely investigated class, due to their versatile biological and pharmacological activities. Plant secondary metabolites are majorly present in fruits and vegetables, as well as in many cereals, tea, coffee, medicinal plants, and several dietary sources, and have sensory and health-promoting properties. Over 8,000 polyphenolic compounds and more than 9,000 flavonoids have been discovered in nature, including antioxidants, anti-inflammatories, cardioprotectives, neuroprotectives, antimicrobials, and anticancer compounds (Ciupei et al., 2024). Moreover, the multitargeted activity of polyphenols, including modulation of oxidative stress and inflammatory signaling pathways, as well as interactions with the intestinal microbiota, further highlights their role in current research on nutraceuticals and therapeutics (Koca et al., 2025). Despite the considerable pharmacological potential of many polyphenolic compounds, their clinical application is constrained by their low oral bioavailability. This constraint arises from multiple physicochemical and biological factors, including inadequate water solubility and restricted intestinal permeability, poor chemical stability in the gastrointestinal environment, rapid metabolism, and high first-pass elimination (Sahoo et al., 2026). Furthermore, many dietary polyphenols are glycosylated/carbohydrated or polymerized, and some are very firmly bound to food matrices and are consequently difficult to absorb systemically (Das et al., 2023). This means that the vast majority of orally ingested polyphenols do not reach their biologically effective concentrations in the systemic circulation and tissues; therefore, there is a considerable discrepancy between in vitro activities and in vivo therapeutic efficacy (Saad et al., 2025). To address these issues, significant effort has been invested in developing more sophisticated delivery systems that can modulate the solubility, stability, permeability, and pharmacokinetic profiles of polyphenolic compounds. Many traditional formulation methodologies have shown promising results in improving oral bioavailability, but they continue to use synthetic surfactants, non-biodegradable solvents and carriers, and energy-intensive processes, which constrain their long-term sustainability and wider translational application (Shirzad et al., 2025).

In this scenario, more sustainable, “greener” strategies are becoming available, offering relevant alternatives to enhance the bioavailability of polyphenolic compounds without harming the environment or causing significant toxic effects. In recent years, improvements in green extraction processes, colloidal systems based on edible excipients, natural biopolymers, protein-polysaccharide assemblies, self-assembled nanotech systems, and conjugation approaches have created new opportunities to formulate bioactives that are safer and more environmentally friendly (Palos-Hernández et al., 2025). Also, the structural diversity and accumulation of these polyphenols are strongly influenced by environmental, geographical, physiological, and genetic conditions during plant development. Factors such as light intensity, temperature, water availability, nutrient status, and biotic or abiotic stress regulate secondary metabolite biosynthesis, resulting in substantial variations in polyphenol composition, yield, and bioavailability, which should be considered when developing green strategies to enhance bioavailability (Özay and Pehlivan, 2024). To further enhance the bio-accessibility and systemic availability of dietary polyphenols, various technologies and biotechnologies (e.g., enzymatic hydrolysis, fermentation, probiotic-assisted transformation, and food matrix modification) are also being investigated (Polia et al., 2022). These are sustainable approaches that improve delivery efficiency and biocompatibility and are aligned with a worldwide trend in the development of nutraceuticals and pharmaceuticals. While many reviews have summarized formulation strategies to improve polyphenol bioavailability, most focus primarily on pharmaceutical performance. There has been comparatively limited attention given to the sustainability of formulation processes, the physicochemical characterization of these compounds, scalability, regulatory aspects, and the translational feasibility of green delivery systems. This review aims to provide a comprehensive and critical evaluation of the newly developed “green” methods designed to enhance the bioavailability of polyphenolic bioactive compounds. It will specifically address effective and sustainable delivery systems, eco-friendly processing technologies, mechanisms underlying improved absorption, environmental considerations, and prospects for future commercialization. Additionally, the review will explore the translation of these strategies into nutraceuticals and therapeutics, as well as future perspectives in this field.

2 New era of green strategies

Traditional methods for enhancing the bioavailability of bioactives, such as polyphenols, have limitations and are not readily accepted as environmentally friendly or safe for human consumption (Zahir et al., 2026). There has been a significant drive to discover new “green” methods of nanoengineering that use sustainable biomaterials, self-assembly principles, and energy-conserving processes. Figure 1 illustrates the challenges faced in polyphenol bioavailability, various green strategies, their advantages, and translational impact. These new green delivery systems can not only enhance the stability, solubility, absorption, and sustained release of polyphenols but also reduce detrimental effects on internal physiological processes and preserve their bioactivity (Kirubakaran et al., 2026). Table 1 summarizes various sustainable systems and their comparative assessment.

TABLE 1. Comparative evaluation of green strategies implemented to boost polyphenol bioavailability.

2.1 Carrier-free delivery

Carrier-free delivery has recently been shown to be an innovative, green approach to addressing the inadequate solubility, instability, rapid metabolism, and limited bioavailability of polyphenols. Unlike conventional nanocarriers, these delivery systems self-assemble from bioactive compounds, eliminating the need for a synthetic carrier and resulting in enhanced drug loading capacity, reduced carrier material toxicity, and improved biocompatibility (Zhou et al., 2026). The principal variables influencing the self-assembly of polyphenols include intermolecular interactions such as hydrogen bonding, π-π stacking, and hydrophobic interactions, as well as oxidative polymerization and metal coordination (Xue et al., 2025). The interactions enable the formation of stable nanoscale architectures that are physico-chemically robust and exhibit controlled release. Recently, oxidative polymerization was shown to be a suitable method for developing pH-responsive carrier-free nanoparticles encapsulating polyphenols that exhibited higher antioxidant activity and gastrointestinal stability, thereby increasing their oral bioavailability (Liu et al., 2024). Likewise, these green synthesis methods, such as the H₂O₂-based method, have provided an environmentally friendly way to prepare Epigallocatechin gallate (EGCG) nanoparticles devoid of toxic substances (Zhou et al., 2026). There has been significant therapeutic potential in carrier-free nanoassemblies for cancer management. It has been observed that polyphenol-based carrier-free nanoparticles exhibit better antioxidant and anticancer properties than free polyphenols, owing to their improved pharmacokinetic behavior (Dewanjee et al., 2023). Synergistic anti-tumour activities with enhanced bioavailability were likewise observed for natural binary polyphenols, tannic acid, and nobiletin, via suppression of tumour growth and stimulation of apoptosis (Wu et al., 2025). Hesperidin and berberine self-assemble spontaneously, forming carrier-free nanoparticles via intermolecular interactions, as shown in Figures 2i,ii. Berberine-hesperidin nanoparticles exhibited improved drug-loading capacity, good self-assembly stability, and a well-defined spherical morphology. The nanoscale assemblage enhanced the absorption, stability, and bioavailability of the phytochemicals upon oral administration, thereby elevating therapeutic efficacy. In ulcerative colitis, oral delivery of these nanoparticles effectively modulated the intestinal immune microenvironment, restored intestinal barrier function, and improved treatment response (Gao et al., 2023). The carrier-free curcumin-anthocyanin (Cur-Ant) nanoparticles represent an emerging green, self-assembled delivery approach to improve the bioavailability. In dextran sulfate sodium (DSS)-induced colitis models, Cur-Ant nanoparticles showed superior localization at the targeted inflammatory site in the colon, with improved accumulation and retention compared to free compounds, as observed in Figure 3. In addition, histopathological and biochemical analyses revealed a good biosafety profile, with no apparent damage to major organs (Xie et al., 2026). Similarly, self-assembled nanomedicines containing flavonoids enhanced antibacterial activity against multidrug-resistant bacteria by disrupting membranes (Zhang M. et al., 2025). Carrier-free delivery systems for polyphenols, however, are a very promising platform, offering improved efficacy and bioavailability while demonstrating good biocompatibility and sustainability.

2.2 Edible colloidal systems

Many polyphenols exhibit poor water solubility and instability in the gastrointestinal tract, thereby limiting their therapeutic efficacy and nutritional value. To address these drawbacks, edible colloidal systems have attracted interest; these food-grade systems enhance the dispersion, protection, and intestinal absorption of hydrophobic bioactives. Typically, these systems are formulated with lipids used in food systems, phospholipids, and natural surfactants, rendering systems that are biocompatible, biodegradable, and suitable for sustainable delivery applications (Mohammadi et al., 2022). Bioactive compounds are typically encapsulated in colloidal carriers, such as nanoemulsions, liposomes, and hydrogels, to enhance their protection against harsh environments and the gastrointestinal tract (Wang B. et al., 2024). Nanoemulsions are among the most widely studied edible colloidal systems because their nanoscale droplets offer a high interfacial area and improved gastrointestinal absorption. The enhanced solubility and dispersion of hydrophobic phytochemicals in nanotechnology enhances their intestinal uptake and bioavailability. The improvement in oral bioavailability of organogel-based curcumin nanoemulsions is achieved through various complementary mechanisms, as demonstrated in Figures 4i–iii. Nanoemulsification enhances curcumin solubilization and facilitates its incorporation into mixed micelles, thereby improving intestinal solubility and subsequent systemic circulation. The bio-accessibility and oral absorption of the nanoemulsion formulation were greater than those of unformulated curcumin, with a significant 9-fold increase in plasma curcumin levels. The results demonstrate the potential of edible colloidal systems to address the issues of inadequate water solubility and limited bioavailability of polyphenols (Yu and Huang, 2012). In another study, nanoemulsions containing echium oil showed greater enhancement of curcumin bioavailability and increased release of beneficial omega-3 fatty acids during simulated digestion (Inal et al., 2022). Also, the anti-inflammatory efficacy of the curcumin-loaded nanoemulsions was greater, with enhanced membrane permeation and protection against rapid curcumin degradation (Pache et al., 2026). There are also formulations that have demonstrated better stability, permeation, and enhanced bioavailability using resveratrol-loaded nanoemulsions (Kotta et al., 2021). Another important colloidal system used for the delivery of polyphenols is liposome systems. Liposomes are vehicles composed of phospholipid bilayers that can entrap amphiphilic compounds, thereby improving their stability and controlled release behavior (Nsairat et al., 2022). Edible liposomal systems are colloidal delivery systems made from food-grade materials that replicate the functions of biological systems to enhance the bioavailability of bioactive compounds. Xu et al. used a green, hydrolysis-based synthesis approach to fabricate a glycerol-based system for encapsulating curcumin via proliposomes, demonstrating improved gastrointestinal stability and enhanced curcumin bioavailability. The capacity to stabilize and increase the bioavailability of flavonoids is also a major advantage of using hydrogels as edible carriers (Xu et al., 2025). Similarly, solid lipid nanoparticles (SLNs) can improve the stability and oral bioavailability of hydrophobic polyphenols. Naringenin loaded into solid lipid nanoparticles (SLNs) achieved a high loading efficiency of 79%–85%, resulting in a 9–12 fold increase in naringenin bioavailability in Wistar rats via the oral route. This enhancement was due to improved gastrointestinal solubility, protection against enzymatic degradation, and enhanced absorption via paracellular or intercellular pathways, thereby overcoming the flavonoid’s poor oral bioavailability (Zaheer et al., 2025). Curcumin-loaded solid dispersion lipid particles (SDLPs) demonstrated the enhancement of intestinal transport of curcumin, which had high EE (82.55%), exhibited sustained drug release, and showed improved ex vivo intestinal permeation through the intestinal mucosa (Apoorva et al., 2025). Also, Wang et al. prepared chitosan-coated curcumin-loaded nanostructured lipid carriers (NLCs), which have demonstrated improved gastrointestinal stability, sustained release of curcumin, its adhesion with mucus, and oral bioavailability in rats by about 1.8 fold higher compared to uncoated NLCs, highlighting the benefits of surface-engineered lipid nanocarriers (Wang C. et al., 2025). Collectively, these findings align with recent studies indicating that natural, food-grade carriers can significantly address the biopharmaceutical challenges posed by poorly soluble polyphenols (Bertoncini-Silva et al., 2024).

2.3 Self-assembled nanoparticles

Self-assembled nanoparticles are an emerging green nanotechnology platform engineered via non-covalent interactions (Pal et al., 2024). The supramolecular assembly properties of polyphenols enable them to form stable nanostructures under mild, environmentally friendly conditions, owing to the presence of catechol and galloyl groups (Liu et al., 2023). Research has confirmed that self-assembled polyphenol nanoparticles exhibit greater physicochemical stability, controlled release properties, and enhanced therapeutic bioavailability (Feng et al., 2025). The creation and use of self-assembled nanoparticles based on polyphenols are shown in Figures 5i, ii. Polyphenols can interact with proteins, polymers, nucleic acids, metal ions, and cell membranes via a variety of non-covalent interactions without the need for a pre-prepared receptor. The interactions result in stable nanostructures without the need for other carrier materials. A representative case is the formation of oligonucleotides into core-shell nanoparticles by EGCG, which results in increased cargo stability, protection of nucleic acids against enzymatic digestion, increased cellular uptake, and enhanced cellular delivery. These self-assembled systems illustrate the potential of polyphenol-based nanoplatforms to enhance drug bioavailability, improve drug delivery efficiency, and enhance therapeutic activity (Shen et al., 2020). Tong et al. synthesized novel, carrier-free sugarcane nanoparticles encapsulating polyphenol using oxidative polymerization and supramolecular-mediated self-assembly, demonstrating superior antioxidant performance, bioavailability, and systemic exposure in vivo compared to free polyphenols (Tong et al., 2026). Likewise, the oral bioavailability of EGCG/PVP-curcumin self-assembled nanoparticles was approximately 12 times higher than that of free curcumin, and the intestinal release of this formulation was pH-responsive (Chen et al., 2022). Self-assembled systems have similarly demonstrated immense potential to leverage the therapeutic properties of natural antioxidants and flavonoids. Han et al. previously reported enhanced effective uptake, ROS scavenging activity, and radioprotective activity of self-assembled EGCG nanoparticles compared with free EGCG (Han X. et al., 2024). Similarly, self-assembled nanoparticles of abietic acid and proanthocyanidin B2 enhanced the thermal stability, gastrointestinal stability, cellular uptake, and in vitro bioavailability of proanthocyanidin B2 due to hydrogen bonding and hydrophobic interactions. This work demonstrates the promise of naturally sourced self-assembling carriers as environmentally friendly carriers of polyphenols (Han Y. et al., 2024).

2.4 Biopolymeric nanoparticles

Due to polyphenols’ involvement in various metabolic reactions and gastrointestinal absorption, and their low aqueous solubility, biopolymeric nanoparticles have emerged as sustainable nanodelivery systems to overcome these drawbacks. These carriers, derived from proteins, polysaccharides, and other sources, exhibit outstanding biocompatibility and biodegradability and are safe for food use; they improve the stability, bioaccessibility, and oral bioavailability of the encapsulated bioactives (Guo et al., 2024). Their functional properties stem from intermolecular forces, especially hydrogen bonding, hydrophobic interactions, and electrostatic attractions, which enable effective packaging and the gradual release of polyphenolics. A major category of biopolymeric carriers studied is protein-based nanoparticles, which are known to be more amphiphilic and to have a higher affinity for hydrophobic phytochemicals. Casein, oat protein, soy protein, zein, whey protein isolate, and bovine serum albumin have all been proven to increase polyphenol delivery. For instance, casein nanoparticles have been used to enhance the bioavailability of quercetin, and oat protein-shelled nanoparticles have been demonstrated to improve the stability and bioavailability of resveratrol (Peñalva et al., 2019). Likewise, whey protein isolate and bovine serum albumin nanoparticles enhanced the protection and absorption of Lycium barbarum polyphenols, demonstrating the versatility of these protein carriers in stabilizing bioactives (Ni et al., 2025). Zeins have been the focus of extensive research and numerous studies due to their hydrophobic properties and superior encapsulation capabilities compared to other plant proteins. The in vivo intestinal transport, plasma levels, and anti-inflammatory activity of resveratrol were enhanced by zein-pectin core-shell nanoparticles compared to the native molecule (Liu et al., 2020). Similarly, Cur extract in zein/HP-βCD nanoparticles was found to be more stable and bioavailable than its native form during stomach digestion, providing the necessary stability and sustained release (Zhang Z. et al., 2024). More recently, the protein-based systems have been extended to oilseed proteins and soy protein isolate. The latter system proved beneficial in two experimental colitis models due to improved bioavailability and therapeutic efficiency of resveratrol when encapsulated into soy protein isolate-polyguluronate nanoparticles, and due to the synergistic protein-polyphenol interaction that was reported to improve bioaccessibility and oral bioavailability of apigenin when incorporated into flaxseed gum oligosaccharide-coated plant protein nanoparticles (Li Z. et al., 2025). Polysaccharide-based nanoparticles offer additional benefits, including mucoadhesive properties, resistance to gastrointestinal degradation, and enhanced epithelial transport. These are effective as chitosan and its derivatives and can easily extend intestinal residence time and improve paracellular absorption. Additionally, gastrointestinal stability and absorption of other flavonoids, including quercetin and catechin derivatives, have been observed with a chitosan-based system. The oral bioavailability of vitexin was significantly improved when encapsulated in chitosan-coated nanoparticles (Lawson, 2023). Likewise, pinonasal chlorophyll, polychlorophyll, and teraxanthin showed increased gastrointestinal stability and colon adhesion. In the same way, Auricularia auricula-derived polysaccharide nanoparticles also increased the gastrointestinal stability of pinonasal polyphenols derived from Pinus koraiensis (Kang et al., 2024). Polysaccharide self-nanoemulsifying systems have also shown a significant increase in the oral bioavailability of poorly soluble flavonoids, such as fisetin (Gunjal et al., 2024). Protein-polysaccharide hybrid nanoparticles are a recent area of research interest because they combine the increasing structural stability of proteins with the mucoadhesive and protective properties of polysaccharides. Nanoparticles prepared from gelatine-finger citron polysaccharide significantly enhanced the gastrointestinal stability and absorption of luteolin, thereby increasing its solubility, bioavailability, and therapeutic efficacy (Wang F. et al., 2024). Similarly, treatment with nanoparticles of sodium caseinate-konjac glucomannan was shown to stabilize, protect against degradation, enhance antioxidant activity, and thereby enhance the bioavailability of anthocyanins, while polysaccharide-coated liposomal nanoparticles with improved protection against degradation enhanced cellular bioavailability and bioactivity of anthocyanins (Zhang H. et al., 2024). The combination of ‘natural’ and ‘engineered’ systems is increasingly recognized as a potential next-generation delivery system for food-grade polyphenols. Biopolymeric nanoparticles exhibit several synergistic mechanisms that enhance polyphenol bioavailability, including improved aqueous dispersibility, enhanced gastrointestinal stability, extended release, enhanced epithelial transport, and enhanced cellular uptake (Munawar et al., 2025). The use of renewable natural materials, along with their excellent safety profile and delivery efficiency, makes them one of the most promising green nanotechnology platforms for future use in nutraceuticals and therapeutic applications. The self-assembly and intermolecular interactions among biopolymeric nanoparticles can be used to design various architectures, such as nanoparticles, nanofibers, nanomicelles, nanogels, and nanocapsules, as shown in Figure 6i. Zein, casein, whey protein, gelatine, and soy protein are examples of proteins that can be used to create matrices for the entrapment of polyphenols, thereby improving their bioaccessibility (Yang et al., 2022). The FESEM images, as shown in Figure 6ii , reveal distinct spherical and aggregated nanoparticles that can efficiently capture polyphenols within the protein network. This structural organization helps to shield polyphenols from degradation in the environment and gastrointestinal tract, allows for controlled release, and enhances their bioavailability and therapeutic effects (Ashwar and Gani, 2024). One challenge is maintaining the structural integrity of nanoparticles without using potentially harmful chemical cross-linking agents. To overcome this limitation, the natural electrostatic layer-by-layer (LbL) methodology has been developed and proved to be an environmentally friendly manufacturing method (Zhang L. et al., 2025). The principle of this approach is to exploit the pH-dependent surface charge of a biocompatible polymer (e.g., gelatine or zein). For example, layers of polyglutamic acid and poly-L-lysine can be built via electrostatic attraction, thereby avoiding the need for synthetic cross-linking agents. These sustainable production processes not only minimize the toxicity of the solvents used in their production but also enhance nanoparticle stability and protect the encapsulated polyphenols from environmental exposure as they travel through the gastrointestinal tract. Table 2 categorizes emerging sustainable biopolymeric nanoparticles used for polyphenol delivery.

TABLE 2. Emerging biopolymeric nanoparticles for sustainable approaches.

2.5 Ionic liquids and deep eutectic solvent-based systems

Ionic liquids (ILs) have generated significant interest because they offer an effective, sustainable, and alternative method for delivering solvents (Jain et al., 2024). The versatility of ILs in their physicochemical properties makes them an ideal platform for enhancing the processing, stabilization, and bioavailability of polyphenolic compounds (Luo et al., 2022). Due to their tunable structure, ILs can influence interactions between bioactive polyphenols, e.g., by modulating hydrogen bonding and aromatic interactions, thereby improving their solubilization and stabilization (Azarhoosh and Pirsa, 2026). Several studies demonstrated that IL-assisted physicochemical enhancement is useful for polyphenols. Chowdhury et al. developed a unique ionic liquid-curcumin complex that substantially enhances the solubility and stability of curcumin in aqueous environments, thereby addressing the critical limitations associated with the low water solubility of polyphenols (Chowdhury et al., 2019). Similarly, researchers reported amino acid ester-based phenolic ionic liquids that markedly enhance luteolin dissolution through various molecular interactions and exhibit greater biocompatibility than conventional IL systems (Shimul et al., 2022). In addition to solubilization, ILs have shown immense potential for the extraction and recovery of polyphenols. Sahne et al. demonstrated that the yield and purity of curcumin from turmeric were significantly improved by enzyme-assisted ionic liquid extraction compared with conventional solvents (Sahne et al., 2017). Imidazolium-based ionic liquids can remarkably enhance the solubility of curcumin in a concentration, temperature, and solvent-dependent manner, as shown in Figures 7i, ii. Curcumin becomes more soluble when the ionic liquid concentration rises because of micellar aggregation and increased intermolecular interactions. In addition, the use of hydroalcoholic media in ionic-liquid-based systems is highly versatile for optimizing the loading and delivery of poorly water-soluble polyphenols at elevated temperatures. The molecular interaction analysis results presented in Figure 7iii also support the role of hydrogen bonding, van der Waals forces, and other non-covalent interactions in the stabilization of curcumin-ionic liquid complexes, which aids in achieving improved solubilization. These effects can synergize to enhance dissolution, gastrointestinal absorption, and oral bioavailability (Li D. et al., 2025). Similarly, Bisht et al. reported that the aqueous solubility of curcumin has been significantly improved by 8,750-fold using a superbase ionic liquid ([mTBNH][OAc]), which also improves the stability of curcumin over time to 385 h, revealing the potential value of ionic liquid-based formulations to overcome the poor solubility and instability of hydrophobic polyphenols (Bisht et al., 2026). In addition to their formulation benefits, ILs and DESs are now recognized as viable substitutes for conventional organic solvents on sustainability grounds, as they are low volatility, have tunable physicochemical properties, require lower solvent consumption, and are potentially recyclable (Acharya et al., 2026). The green assessment presented in Figure 7iv is also a key point, highlighting the environmental compatibility of the mentioned assisted processes, which are to be used as a multifunctional platform for the efficient removal, extraction, and delivery of polyphenols, as well as for environmentally friendly formulation approaches (Li D. et al., 2025). The potential of natural deep eutectic solvents (NADES) to significantly improve the oral bioavailability of polyphenols is becoming increasingly evident (Bajirao Patil and Patil, 2026). Faggian et al. demonstrated improved plasma exposure and increased circulation time of rutin encapsulated in a proline-based NADES compared to the aqueous suspension (Faggian et al., 2016). da Silva et al. showed that, in addition to flavonoids and isoflavones, a choline chloride: glycerol acid NADES increased the bioavailability of blueberry extract anthocyanins by 140% and enhanced phenolic stability during gastrointestinal digestion (da Silva et al., 2021). Similarly, Uka et al. reported that the solubility and antioxidant activity of resveratrol could be significantly improved using the choline chloride-based NADES systems (Uka et al., 2023). In the case of delivering flavonoids, Dangre et al. found that a choline chloride-glycerol (1:3) deep eutectic solvent (DES) significantly improved the solubility (232.56 mg/mL), intestinal transport, and oral bioavailability of naringin (Dangre et al., 2023). However, recent research has focused on the need to develop safer, truly sustainable solvent systems, ideally by synthesizing ionic liquids and NADES with biodegradable, biocompatible components that minimize potential toxicity while maintaining extraction and formulation efficiency (Rosa et al., 2026).

2.6 Physicochemical characterization of green nanoformulations

A crucial assessment of the quality, stability, and biological activity of green nanoformulations for the optimization of polyphenols bioavailability relies on the physicochemical characterization, as they affect the encapsulation efficiency of the biomolecules, the stability in the digestive systems, and the rate of drug release from the green nanocarriers (Pattnaik and Swain, 2025). Extensive material characterization, in turn, establishes correlations between formulation properties and functional performance, enabling the rational design and optimization of sustainable delivery systems (Altammar, 2023). Dynamic light scattering (DLS) is a widely used technique for measuring hydrodynamic particle size and the polydispersity index (PDI), providing vital insights into particle-size distribution and formulation uniformity in solution. Dual-loaded polyphenol micelles exhibited>98% entrapment efficiency, a narrow particle-size distribution in the nanometer range, stable physicochemical properties, and retained efficacy in formulations for up to 7 days of storage, demonstrating the suitability of DLS characterization for assessing formulation quality (Guedes et al., 2026). Likewise, isoorientin was entrapped in zein/gum arabic nanoparticles, which exhibited good uniformity (mean particle size, 149.31 ± 2.31 nm, PDI, 0.31 ± 0.01), suitable oral delivery potential, and good colloidal stability (zeta potential, −55.21 ± 0.64 mV). The absence of crystalline peaks after encapsulation was also confirmed by X-ray diffraction (XRD), indicating amorphization of the polyphenol in the carrier matrix (Yang et al., 2024). Complementary methods such as X-ray Diffraction (XRD) and Differential Scanning Calorimetry (DSC) can be used to characterize the formulation’s crystallinity, thermal stability, and integrity during development (Tripathy and Srivastav, 2025). Morphological analyses further demonstrated that the spherical nanoparticles are uniformly distributed with smooth surfaces. Characterization by transmission electron microscopy (TEM), field-emission scanning electron microscopy (FESEM), and atomic force microscopy (AFM) allows direct visualization of particle size and surface architecture, thereby confirming the structural integrity of the nanoformulations (Dzyhovskyi et al., 2024). Fourier transform infrared (FTIR) spectroscopy is widely used to detect specific functional groups and to confirm hydrogen bonding, electrostatic interactions, and other intermolecular interactions, thereby enabling polyphenols to be effectively encapsulated within carrier matrices (Pasieczna-Patkowska et al., 2025). Furthermore, FTIR is a complementary analytical tool for assessing surface properties, changes in functional groups, the compatibility between bioactive molecules and formulation materials during formulation development (Kumar et al., 2026). Molecular-level information on chemical composition, molecular organization, lipid dynamics, cargo encapsulation, and interactions between the drug and the carrier, which goes beyond the conventional physicochemical approach, is also provided by nuclear magnetic resonance (NMR) spectroscopy (Ueda, 2025). In conclusion, thorough physicochemical characterization is crucial for improving green nanoformulations and maximizing polyphenol bioavailability. Future advancements will depend on the development and standardization of analytical procedures that ensure reproducibility, quality control, regulatory compliance, and effective clinical translation, as well as on formulation design.

3 Mechanistic assessment of improved bioavailability of polyphenols

The oral bioavailability of polyphenols is, in general, extremely low, attributed to food matrix interactions, low gastrointestinal stability, limited intestinal absorption, high phase I and phase II metabolism, and gut microbiota biotransformation, and is controlled by a complex interplay among different physicochemical properties (Di Lorenzo et al., 2021). Figure 8 illustrates the polyphenol metabolism and absorption pathway in the human intestine (Mahdi et al., 2025). The food matrix significantly influences the release and absorption of polyphenols. Tarko et al. found that, in simulated digestion, 5%–9% of polyphenols of whole fruits were bioavailable, while 14%–58% of polyphenols in fruit extracts were released. Furthermore, 5%–44% of polyphenols are not released during digestion, indicating that the retention is affected by the undigested food matrix and has an important effect on polyphenol (Tarko and Duda-Chodak, 2020). The following factors contribute to the reduction of the fraction of ingested polyphenols that can enter systemic circulation: (1) low aqueous solubility, (2) instability in the gastrointestinal tract (GIT), (3) restricted membrane permeability, and (4) extensive metabolic transformation. Thus, current strategies for enhancing green bioavailability focus on sustainable, food-grade, biocompatible systems that facilitate the delivery of polyphenols to target sites and tissues. The primary intrinsic structural features of polyphenols, such as size, polarity, glycosylation, and conjugation status, strongly determine a molecule’s behavior in the intestine and its pharmacokinetics (Stromsnes et al., 2021). Before being absorbed, polyphenols must be liberated from the food matrix and remain stable during the digestive process. Flavonoids and anthocyanins, however, are subject to significant degradation in the small intestine and, consequently, to reduced bioavailability (Tagliazucchi et al., 2010). To overcome this issue, green encapsulation technologies are proposed that protect bioactive compounds from pH changes, enzymatic hydrolysis, and oxidation. For example, the oral absorption of curcumin was markedly enhanced by increasing its aqueous solubility through encapsulation in solid lipid nanoparticles, as demonstrated by a significantly elevated AUC (124.2 ± 2.5 vs. 1.78 ± 0.7 h·ng/mL), a higher Cmax (55.75 ± 2.5 vs. 1.18 ± 0.3 ng/mL), a reduced Tmax (1.0 vs. 2.0 h), and an approximately 70-fold increase in oral bioavailability compared to free curcumin (Gupta et al., 2020). Protein-carriers and polysaccharide-carriers have been recognized as among the most promising carriers, as they are biodegradable, food-compatible, and provide intestinal stability (Grgić et al., 2020). Among these systems, zein-based nanoparticles have demonstrated strong efficacy in preserving polyphenol integrity during digestion. In a zein-whey protein isolate (WPI) nanoparticle system developed for oat bran polyphenols, the mean diameter of a polymeric particle was 108.6 ± 4.3 nm, and the bioaccessibility of the polyphenols in the formulation was 73.3% compared to <34% for non-encapsulated polyphenols (Mylvaganam et al., 2026). The nanoparticles were also found to be stable over a range of pH, ionic strength, and temperature, indicating their compatibility as strong food carriers. Likewise, the zein-tea polyphenol-pectin ternary nanoparticles had an encapsulation efficiency of about 94.2%, a particle yield of over 95%, and remained stable over a pH range of 2-8 and an ionic strength of up to 500 mM (Wang et al., 2021). The nanoparticles released their contents in a sustained manner during simulated gastrointestinal digestion, minimizing degradation and thus enhancing the phenolic fractions available for absorption. In general, these results show that improved protein bioavailability can be achieved by simultaneously enhancing its stability, protection, and controlled release through protein-polysaccharide interactions. Another important mechanism accounting for bioavailable enhancement is solubility and dissolution. The limited aqueous solubility has been a major drawback for many flavonoids, including quercetin, curcumin, and other lipophilic compounds. The protein-based delivery system enhances the product’s solubility by increasing dispersion and decreasing crystallinity. Quercetin was more soluble in whey protein-loaded complexes when preheated (0.047 g/L) than in native quercetin (0.039 g/L). In addition, the gastrointestinal retention values for Quercetin powder obtained by lyophilization and spray drying were 76.0% and 64.1%, respectively, suggesting better protection against gastrointestinal degradation. These enhancements were suggested to result from strong protein-polyphenol interactions that protected quercetin in the carrier matrix and boosted its dissolved fraction in the intestine for uptake (Ji et al., 2025). In Figure 8, the mechanism responsible for the increased bioavailability of polyphenols is shown. Nanoparticle-mediated delivery led to a significant improvement in the cell internalization of the model flavonoid compared to the non-encapsulated form, as demonstrated in Figure 9i, suggesting enhanced interaction with biomembranes and consequent higher intracellular accumulation. The uptake efficiency increased over time, indicating efficient endocytic internalization of the nanocarriers. It also illustrates greater intestinal penetration after oral administration, with increased fluorescence intensity in intestinal tissues, further supporting increased transport across the gastrointestinal barrier. These enhancements directly affect absorption and pre-systemic losses, thereby improving efficiency. The plasma concentration time profiles in Figure 9ii show significantly higher plasma concentration after nanoencapsulation, which yields extended plasma exposure (AUC) by a significant amount, with increased Cmax. Together, these findings demonstrate that nanoscience-based delivery systems can improve polyphenol bioavailability through a variety of complementary mechanisms, culminating in greater therapeutic efficacy (Kadari et al., 2017). Edible colloidal systems are especially appealing because they use matrices commonly used in food and are easily incorporated into functional foods and nutraceuticals. Zheng et al. encapsulated curcumin, quercetin, and resveratrol in their plant-made milk system, achieving 80%–100% encapsulation efficiency. The retention values of resveratrol after simulated gastrointestinal digestion are 80%–90%, while those of curcumin and quercetin are 65%–70% and 20%–30%, respectively, which are significantly higher than those of the non-encapsulated counterparts (Zheng et al., 2023). This was thought to be due to better incorporation of polyphenols into mixed micelles formed during lipid digestion, thereby increasing their bioavailability. Innovative green platforms, called natural deep eutectic solvents (NADES), improve bioavailability through two concurrent actions: solubility and stability. This extensive network of hydrogen bonding within NADES enables the dissolution of poorly soluble compounds and prevents degradation. In comparison with conventional preparation, the bioavailability of anthocyanins from the conventional preparations and from the NADES (based on choline chloride) was enhanced by about 140% and by 124%, respectively, and the gastrointestinal stability during digestion was improved significantly in the former compared to the latter (da Silva et al., 2021). NADES are mixtures of correctly formulated, biodegradable, naturally occurring constituents, thereby offering highly favorable compatibility with sustainable formulation strategies. The microbiota-mediated biotransformation of dietary polyphenols is also important for their bioavailability. Due to its high GI, a significant portion of polyphenols is not absorbed until they reach the colon, where microbial enzymes break them down into smaller units with better absorption potential (Wang et al., 2022). This process can prolong the biological activity of polyphenols well beyond the initial digestion stage. With intestinal bioavailability values of almost 79%, the chosen strains of Lactobacillus and Bifidobacterium increased the bioaccessibility of catechins by over two decades (Tkacz et al., 2025). Results like these indicate that modulation of microorganism activity could significantly influence the release and transformation of poorly available polyphenols and also have beneficial effects on gut health. Overall, available evidence suggests that green bioavailability-enhancement strategies have multiple complementary mechanisms of action and do not operate through a single pathway. Protein-based carriers, protein-polysaccharide nanoparticles, edible colloidal systems, NADES, and microbiota-directed approaches facilitate enhanced polyphenol bioavailability by increasing solubility, improving gastrointestinal stability, mitigating degradation, enabling controlled release, promoting micellar incorporation, and enabling microbial biotransformation (Mylvaganam et al., 2026). Through these synergistic mechanisms, green delivery systems significantly enhance the bioavailability of polyphenols for absorption and serve as a foundation for developing polyphenol-rich formulations into functional foods, nutraceuticals, and potential future therapeutics. Table 3 summarizes various polyphenols using green strategies and their bioavailability outcomes.

TABLE 3. Bioavailability enhancement of different polyphenols using a green strategy.

4 Bridging the gap between bioavailability enhancement and translational parameters

Although there have been considerable strides in sustainable bioavailability-enhancement strategies, improvements in pharmacokinetics don't necessarily translate into improvements in therapeutic response. In fact, the so-called translational paradox has been a major barrier to the development of polyphenol-based nutraceuticals and therapeutics (Vrankova et al., 2026). After absorption, most polyphenols are extensively metabolized into phase I/phase II metabolites, resulting in low blood concentrations of the parent molecules. Exposure to plasma, therefore, does not always result in improved biological activity at target organs (Scott et al., 2022). Additionally, gut microbiota is crucial to the fate of dietary polyphenols. Beslo et al. found that the amount of polyphenols in the large intestine after ingestion ranges from about 90% to 95%, but the metabolites formed may differ significantly from the original polyphenols due to differences in bioavailability. The metabolic pathways of distinct species and individuals make it difficult to translate preclinical research to clinical consequences. Further challenges to successful translation arise from differences between animal models and humans. The PK properties of probiotics can differ among individuals, and the in vivo profile may be difficult to predict from preclinical research (Bešlo et al., 2023). Hence, testing human PK is essential to assess the usefulness of bioavailability-enhancement strategies. Fortunately, a few clinical studies have shown that enhanced forms of polyphenols can significantly increase their bioavailability when administered orally. A hydrogel-based fisetin formulation resulted in 26.9-fold (AUC) and over 23-fold (Cmax) higher fisetin exposure than the unformulated fisetin and time course of fisetin vs. geraldol plasma concentration, with the area under the curve represented in Figure 10i. It is worth noting that a bioavailability-enhancing formulation for oral delivery of fisetin has been shown to produce a translational effect (Krishnakumar et al., 2022). Likewise, trans-resveratrol bioavailability in healthy volunteers was increased by micellar solubilization, resulting in an AUC almost 5 times higher and a Cmax 10.6 times higher (Calvo-Castro et al., 2018). Additionally, an optimized resveratrol formulation demonstrated better pharmacokinetic properties, with 4.8-fold and 1.7-fold increases in Cmax and AUC, respectively, compared with a conventional formulation (Wang J. et al., 2025). Clinical studies demonstrated that curcuminoid formulations with water as the dispersant medium exhibited significantly greater absorption than conventional turmeric extracts, indicating that formulation design is a crucial factor for overcoming turmeric’s bioavailability limitations. Clinical studies also indicated that formulations using water rather than standard turmeric extract showed significantly better absorption, suggesting that formulation design was critical for overcoming turmeric’s bioavailability limitations (Thanawala et al., 2024). Another translational promising route of delivery is food-based systems. Santana et al. showed high intestinal absorption of blueberry polyphenols when consumed in food matrices, both as whole berries and as a protein bar with additional flavoured ingredients (Santana et al., 2025). This indicates that polyphenolic food matrices offer a promising application, with proper matrix design, for the sustainable delivery of polyphenolic bioactives into the intestines. In this regard, Figure 10ii shows the potential of the carrier-free polyphenol nanoparticles to overcome the major limitations related to the oral administration of polyphenols. The self-assembled nanoparticles have demonstrated greater gastrointestinal stability than their free polyphenols and high bioaccessibility in the intestine. Remarkably, gastric and intestinal digestion did not significantly degrade polyphenols, with higher levels observed in the nanoparticle formulations. Among the systems assessed, the highest bioaccessible fraction was observed for tannic acid nanoparticles. The results showed that the gastrointestinal stability and intestinal bioavailability of polyphenols could be enhanced by using carrier-free self-assembled nanostructures, which represent a promising green strategy to optimize polyphenol oral bioavailability and therapeutic benefits (Liu et al., 2024). Joseph et al. demonstrated a natural, self-emulsifying, reversible hybrid-hydrogel formulation of quercetin (FQ-35) that enables translational progress. This study used healthy volunteers in a randomized, double-masked, crossover design to compare the pharmacokinetic profile of formulated quercetin (FQ-35) with that of unformulated quercetin (UQ), which is illustrated in Figure 11. The in vitro release profile indicated that FQ-35 exhibited sustained, pH-independent dissolution, whereas unformulated quercetin showed minimal dissolution under the same conditions. This was attributed to the incorporation of quercetin-loaded micelles within the fenugreek galactomannan hydrogel matrix that increased the aqueous dispersibility and kept the flavonoid in a solubilized state. The plasma concentration-time profiles showed significantly higher concentrations in humans, consistent with the improved physicochemical properties observed there. FQ-35 significantly exceeded UQ in plasma quercetin levels during the 24 h monitoring period, suggesting better intestinal absorption and longer systemic retention. The pharmacokinetic analyses showed 62.08-fold and 18.61-fold improvements in total and free quercetin bioavailability, respectively, compared with the unformulated compound. In addition, the formulation resulted in a prolonged elimination half-life, a delayed T_max, and a higher C_max, indicating prolonged absorption and circulation. The results highlight the power of formulation-driven improvements in solubility and release kinetics to translate into human pharmacokinetic performance, confirming the ability to bridge the gap between strategies for bioavailability enhancement and clinically relevant translation (Joseph et al., 2022). Most clinical studies, however, focus on pharmacokinetic properties rather than long-term therapeutic endpoints, such as Cmax. Future studies should therefore incorporate bioavailability assessments with efficacy biomarkers, tissue distribution studies, and well-designed clinical trials to determine whether this increased bioavailability leads to clinically significant improvements. While clinical validation remains limited, some green bioavailability-enhancing strategies have shown potential for clinical translation in human studies (Table 4 ). The translation of ideas into commercially viable products for polyphenol delivery to enhance bioavailability has yet to occur, despite the considerable advances in sustainable delivery systems. However, given the number of patent registrations, there is a growing effort to address this challenge by developing green delivery technologies that overcome the major barriers to bioavailability. A few representative patents are summarized in Table 5.

TABLE 4. Clinical studies supporting green polyphenol bioavailability methods.

TABLE 5. Summary of patents utilizing green strategies.

5 Limitations of the currently available sustainable methods

Deep eutectic solvents (DESs), natural deep eutectic solvents (NADESs), nanoemulsions, phytosomes, biopolymeric nanoparticles, protein-polysaccharide complexes, and carrier-free nanodelivery systems are examples of green approaches that have shown great promise in improving solubility, stability, and permeability, and in enhancing therapeutic efficacy, while reducing reliance on conventional organic solvents. However, a trend shows that just because they are “green,” sustainability and safety cannot be guaranteed. One of the primary issues is the safety of DESs and related solvent mixtures. But DESs are often described as non-toxic, and the toxicity of the products they yield can vary widely depending on the solvent used. DES biodegradability is a major concern, as it has been linked to toxicity (Martínez et al., 2022). Thus, Juneidi et al. reported greater cytotoxicity for some choline chloride-based DESs than their constituent components, indicating a synergistic effect after eutectic formation (Juneidi et al., 2016). Although DES formulations showed potentially favorable biodegradability, significant differences in cytotoxicity were observed. Radosevic et al. reported more significant differences in the mode of toxic response across various biological models tested (Radošević et al., 2015). The overall results suggest that toxicity testing of the compound remains crucial before extensive use. Furthermore, numerous approaches that enhance bioavailability depend on nanotechnology-based delivery vehicles, which also pose limitations. The diminutive size and extensive surface area of nanoparticles facilitate enhanced interactions with cells, potentially augmenting their bioavailability and elevating their biological reactivity. Exposure to nanoparticles has been correlated with oxidative stress, inflammation, mitochondrial dysfunction, membrane damage, and genotoxicity (Kumar et al., 2025). Xuan et al. also detailed the mechanisms underlying the generation of reactive oxygen species, DNA damage, apoptosis induction, immune dysfunction, and epigenetic changes (Xuan et al., 2023). Furthermore, the long-term clearance of nanoparticles, their accumulation, and their effects on chronic safety in the liver, spleen, lungs, and brain are concerns due to uncertainty about their biodistribution, accumulation, and clearance. High energy demands also limit the sustainability of green technologies. Additionally, energy-intensive and complex methods such as microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE), spray drying, freeze-drying, and high-pressure homogenization can reduce solvent use but also entail challenges related to energy use and infrastructure. The extraction efficiency and time could be enhanced by using MAE, as shown by Kaderides et al., while the extraction outcome is strongly affected by the microwave power, extraction time, solvent composition, and optimization of the process, as demonstrated by Kaderides et al. (2019), Saleem et al. (2024). Likewise, Cheng et al. reported that extraction techniques significantly affect phenolic profiles and antioxidant properties. So, solvent reduction may not necessarily be a good indicator of overall environmental sustainability (Cheng et al., 2023). Another constraint is the labile nature of polyphenols during extraction, processing, and storage. Polyphenols are highly labile to oxidation and hydrolysis and are sensitive to photodegradation and thermal damage. Advanced extraction technologies can increase recovery but can also promote the degradation of sensitive compounds. Researchers compared and contrasted the activity of UAE with traditional extraction, demonstrating that the former is more effective but produces certain polyphenols as byproducts (Belwal et al., 2022). This instability can lead to a loss of bioactivity, affect therapeutic activity, and reduce the real benefits of sustained delivery systems. Other obstacles are reproducibility and standardization. Variability in plant source, geographical origin, cultivation practices, harvest methods, and extraction methods can contribute to differences in extraction efficiency, particle size, particle size distribution, particle-release properties, and biological activity. Moreover, in DES systems, solvent selection is important, as different solvent forms can exhibit significantly different extraction efficiencies (Alsaud et al., 2021). The extraction efficiency of DESs is highly dependent on operating conditions and DES composition, underscoring the potential of DES preparation to achieve process reproducibility and standardization (Qin et al., 2022). A major issue is also the potential for industrial scale-up. Despite numerous laboratory-successful sustainable systems achieving satisfactory results, their implementation for commercial production is constrained by process complexity, high production costs, and instability issues. Moreover, the sustainability measure should address not only solvent replacement but also life-cycle assessment, resource efficiency, environmental impact, and long-term societal benefits (Richardson et al., 2025). Overall, polyphenol bioavailability enhancement techniques have significant potential but are currently limited by concerns about toxicity, particle-related risks, energy requirements, polyphenol instability, lack of reproducibility, scalability issues, regulatory uncertainty, and limited long-term safety data. These limitations will need to be addressed through rigorous toxicological studies, standardized production procedures, life-cycle analyses for sustainability, and thorough clinical testing to enable the successful translation of truly sustainable polyphenol delivery systems. Table 6 presents key limitations linking the translational challenge of sustainable methods for enhancing the bioavailability of polyphenolic compounds.

TABLE 6. Key limitations linking the translational challenge of the currently available sustainable methods.

6 Energy requirements and economic considerations for scaling up green technologies

The sustainability of green formulation technologies should not be evaluated solely by replacing hazardous organic solvents with environmentally friendly alternatives. A green process must be energy efficient, waste-free, resource-efficient, and emission-free, and it must also maximize material efficiency, in accordance with the principles of green chemistry (de Oliveira et al., 2024). So, the quantitative sustainability metrics should be used to assess the environmental performance of extraction and formulation technologies (not only solvent reduction). The atom economy, reaction mass efficiency, E-factor, and Life Cycle Assessment (LCA) are metrics that can provide a more complete picture of a process’s sustainability by addressing material efficiency, waste generation, and the overall environmental impacts of manufacturing (Gallego-Villada, 2025). LCA is one of the most complete environmental impact assessment (EIA) tools for the pharmaceutical and food-processing technologies. Unlike traditional assessments, LCA follows the entire product life cycle, from sourcing raw materials and manufacturing to transport, product use, and end-of-life disposal, and includes the impacts of energy use, greenhouse gas emissions (GHGs), water use, and waste generation (Autzen Virtanen et al., 2026). Therefore, using less toxic solvents without accounting for other environmental impacts could be just as harmful as using them before, because it doesn’t make the overall process more sustainable (Satta et al., 2024). Microwave-assisted extraction (MAE) and ultrasound-assisted extraction (UAE) offer advantages, but each also has specific limitations. Generally, these methods exhibit higher extraction and recovery efficiencies for bioactive compounds, shorter extraction times, lower solvent use, and lower thermal degradation than conventional extraction methods (Melikoglu, 2025). Comparative evaluations have also shown that both optimized MAE and optimized UAE can reduce the energy consumption and related carbon emissions under optimized laboratory conditions (Bodea et al., 2025). However, the overall sustainability of their operations depends not only on reducing solvent use but also on process optimization, equipment efficiency, electricity source, extraction scale, and operating conditions. Therefore, the energy savings obtained in the lab may not translate to the industrial scale, as larger material volumes and continuous operations may significantly increase total energy consumption (Nayak et al., 2026). While green formulation technologies can show promising laboratory performance, scaling them up is a significant challenge. Industrial applications require specialized equipment, additional investment, increased energy use, and ongoing process optimization, which can affect manufacturing costs and commercial viability. In addition to the environmental assessment, a techno-economic analysis should be conducted to ensure that the green technology is economically viable for large-scale production (Singh et al., 2025). In conclusion, the future development of green polyphenol formulation technologies should adopt integrated sustainability frameworks that encompass green chemistry principles, LCA, energy efficiency, quantitative green metrics, and techno-economic analysis beyond solvent replacement, thereby ensuring environmental sustainability (Autzen Virtanen et al., 2026).

7 Challenges from bench to bedside in adopting green strategies

Progress has been made toward a green approach to improve the bioavailability of phenols; however, the application of such strategies in the market remains limited. Despite this, new and improved protein- and polysaccharide-based nanocarriers, edible colloidal systems, self-assembled nanoparticles, and carrier-free formulations have shown improved absorption, stability, and solubility. However, issues remain regarding their reproducibility, regulatory approval, safety evaluation, and scale-up to industrial levels (Ahmed et al., 2026). One disadvantage is the inconsistency in production procedures (Syed et al., 2026). The physicochemical properties and performance of green delivery systems are highly dependent on biological raw materials, extraction methods, and processing conditions, which may lead to batch-to-batch variations and pose challenges for quality control in large-scale manufacturing (Rabiee, 2025). One challenge is the lack of standardized physicochemical characterization and reporting protocols for green nanoformulations, which makes it difficult to consistently assess formulation quality across studies (Sharifi et al., 2022). Characterization, from a translative perspective, should define critical quality attributes (CQAs) using orthogonal analytical methods to ensure batch-to-batch consistency and regulatory compliance during scale-up (Patel and Sanap, 2026). In addition, combining several complementary analytical techniques provides a more complete and accurate evaluation of nanoparticle quality than using a single technique (Yazdanpanah et al., 2026). Finally, the lack of harmonized characterization standards and reporting processes constrains reproducibility, interlaboratory comparability of nanoformulations, their regulatory acceptance, and the successful clinical translation of green polyphenol nanoformulations (Sharifi et al., 2022). Further, regulations for nano-enabled and green delivery remain fragmented. Many countries use existing food, feed, chemical, and/or pharmaceutical regulations to manage such products, but this approach lacks consistency in definitions, safety standards, characterization techniques, and approval procedures (Amenta et al., 2015). The use of appropriate safety evaluators remains a critical issue. While most materials derived from green resources are less toxic, several factors affect toxicity, including the route of exposure, material surface properties, and morphology and particle size (Singh et al., 2023). Hence, in vitro, in vivo, and life-cycle assessments must be conducted to address potential risks, such as oxidative stress, inflammation, genotoxicity, bioaccumulation, and environmental persistence (Rodríguez-Gómez et al., 2025). In conclusion, commercialization of green bioavailability-enhancing technologies will require standardization of manufacturing processes, robust quality control procedures, harmonized regulations, and comprehensive sustainability evaluations to deliver safe, reproducible, and scalable products.

8 Future prospects and conclusion

Although green strategies to improve the bioavailability of polyphenols are well advanced, numerous challenges remain before they are translated into large-scale clinical use and commercialization. Further research should be directed towards scaling up, developing sustainable delivery systems, and developing potential cost-effective vehicles for delivering polyphenols, all using food-grade proteins, polysaccharides, and lipids, as well as other naturally derived materials. A deeper insight into the interactions among polyphenol-loaded carriers, the gastrointestinal environment, and the gut microbiota is also required, as all play important roles in the absorption and biological activity of polyphenols. In addition, there is a need to standardize bioavailability and pharmacokinetic studies, as well as therapeutic response, to enable comparison of results across studies. Although the preliminary evidence is promising, the current research has several drawbacks. The majority of studies examining the delivery of green polyphenols have been conducted in vitro or in small-animal models, with few well-designed human clinical studies. Moreover, the composition and characterization of formulations, the methods used to assess bioavailability, and the experimental models used in the studies make direct comparisons between studies difficult and hinder the establishment of universal design principles. Standardized protocols, comprehensive comparative studies, and clinically relevant assessments will be critical to accelerating the successful translation of green polyphenol delivery systems. The key to moving this from the bench to the bedside will be integrating advanced formulation methods, human clinical testing, customized nutrition plans, and regulatory requirements. This will help develop safer, more effective, and sustainable polyphenol-based nutraceuticals and therapeutics, and their expected progression in green bioavailability is presented in Figure 12. New methods (ionic liquids, NADES, nanoemulsions) are anticipated to further develop and transition to hybrid, sustainable platforms based on protein-polysaccharide complexes and protein-NADES-based nanocarriers. New smart delivery technologies, such as stimuli-responsive and targeted delivery systems, have the potential to further enhance site-specific release and therapeutic activity. AI-driven, data-based formulation design and optimization are likely to further expedite formulation optimization and drive the clinical translation of more efficient, personalized formulations in the future. As a whole, they illustrate a transition from traditional systems to smarter, more sustainable, and clinically relevant systems having translation potential.

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Footnotes

Edited by: Nazimah Hamid, Auckland University of Technology, New Zealand

Reviewed by: Arif Nur Muhammad Ansori, Virtual Research Center for Bioinformatics and Biotechnology, Indonesia

Cennet OZAY, Izmir Kâtip Çelebi University, Türkiye

Footnotes

AUC, Area Under the Curve; DESs, Deep Eutectic Solvents; EGCG, Epigallocatechin Gallate; GI, Gastrointestinal; ILs, Ionic Liquids; NADESs, Natural Deep Eutectic Solvents.