Phytosomes: An Emerging Nanocarrier System for Enhancing the Bioavailability of Quercetin

Over the past few decades, there has been an increasing global interest in natural polyphenols due to their wide-ranging health benefits and therapeutic potential against chronic diseases such as cardiovascular disorders, neurodegenerative conditions, diabetes, and cancer. Among these bioactive compounds, quercetin has attracted significant attention because of its strong antioxidant, anti-inflammatory, and anticancer properties.[1,2] Quercetin is widely found in fruits, vegetables, and medicinal plants such as onions, apples, and tea, and is considered one of the most abundant flavonoids in the human diet. Despite its potent biological activities, its clinical use remains restricted, primarily because of its poor aqueous solubility, limited absorption, and rapid metabolic degradation after oral administration.[3] Quercetin’s therapeutic potential is hindered by its biopharmaceutical limitations. Being highly lipophilic, it dissolves poorly in water and therefore exhibits low gastrointestinal absorption. Once ingested, a large portion of quercetin undergoes enzymatic degradation and extensive first-pass metabolism in the liver and intestines, resulting in minimal systemic availability. Consequently, only a small fraction of the ingested dose reaches the target tissues in its active form. This challenge has prompted researchers to develop innovative formulation strategies aimed at improving the solubility, stability, and bioavailability of quercetin.[4] Several conventional approaches have been explored to enhance the absorption of poorly soluble compounds like quercetin. Micronisation and nanosizing have been employed to reduce particle size, thereby increasing surface area and dissolution rate. Other approaches, such as forming inclusion complexes with β-cyclodextrin or encapsulating quercetin within polymeric nanoparticles and liposomes, have shown moderate success in improving solubility and absorption. However, these methods often face challenges such as physical instability, low drug loading capacity, and complex production processes. Additionally, while liposomes and polymeric nanoparticles can enhance permeability, they sometimes fail to achieve sustained release or optimal interaction with biological membranes, limiting their overall efficiency.[5] To overcome these shortcomings, phytosome technology has emerged as a next-generation nanocarrier system designed to improve the pharmacokinetic performance of plant-derived compounds. Phytosomes are unique phospholipid complexes in which the bioactive phytoconstituent forms a molecular association with phosphatidylcholine or similar phospholipids. Unlike conventional liposomes, where the active compound is merely trapped inside the vesicle, phytosomes form a chemical bond, such as hydrogen bonding between the polar functional groups of the bioactive molecule and the polar head of the phospholipid. This interaction enhances the lipophilicity of the compound and enables better integration with biological membranes, facilitating more efficient absorption and systemic availability.[6] By mimicking the structure and behaviour of biological membranes, phytosomes offer several distinct advantages. They provide improved solubility and stability, protect the encapsulated compound from degradation, and promote efficient intestinal uptake. The lipid-compatible nature of phytosomes also allows the complex to pass more easily through the lipid-rich cell membranes of the gastrointestinal tract. This results in improved pharmacokinetic parameters such as higher peak plasma concentrations, prolonged circulation time, and enhanced therapeutic efficacy. For quercetin, phytosomal encapsulation has been shown to significantly increase its oral bioavailability compared to free quercetin or traditional delivery systems.[7] Given these benefits, the development of quercetin-loaded phytosomes represents a major advancement in natural compound delivery technology. This innovative approach bridges the gap between formulation science and therapeutic application, providing a viable strategy for translating quercetin’s promising biological activities into clinically effective outcomes.[8] The scope of this review is to provide a comprehensive overview of phytosomes as an emerging nanocarrier system for improving the bioavailability of quercetin. It will integrate insights from formulation design, mechanistic studies, pharmacokinetic evaluations, and clinical evidence to present a holistic understanding of how phytosome technology enhances quercetin’s therapeutic potential. Ultimately, this review aims to establish phytosomes as a powerful platform for the efficient delivery of natural polyphenols, paving the way for their broader application in chronic disease prevention and management.

1. Quercetin: Structure, Pharmacology, and Limitations

Quercetin, chemically known as 3,3′,4′,5,7-pentahydroxyflavone, is a naturally occurring polyphenolic flavonol with the molecular formula C??H??O?. Structurally, it consists of a three-ring system (A, B, and C rings) characteristic of the flavonoid family, with five hydroxyl groups strategically positioned at the 3, 5, 7, 3′, and 4′ carbon atoms. This arrangement confers quercetin its strong antioxidant capacity by enabling efficient donation of hydrogen atoms or electrons to neutralize reactive oxygen species (ROS). The presence of conjugated double bonds and multiple hydroxyl substitutions enhances its radical-scavenging and metal-chelating properties, which are central to its biological activity.[9]

Natural Sources

Quercetin is one of the most abundant flavonoids found in the human diet and is widely distributed in various plant-based foods. Major dietary sources include onions, apples, berries, citrus fruits, cherries, grapes, kale, broccoli, and tea leaves. Its content varies depending on factors such as plant variety, cultivation conditions, and food processing methods. For example, onions and apples are particularly rich in quercetin glycosides, while berries and leafy vegetables contain both free and conjugated forms. Quercetin is usually present as glycosides, where sugar moieties such as glucose or rhamnose are attached to the hydroxyl groups, influencing its solubility and absorption profile.[10]

Pharmacological Activities

Quercetin exhibits a wide spectrum of pharmacological activities, making it a key compound in nutraceutical and therapeutic research.

• Antioxidant activity: Quercetin acts as a powerful scavenger of free radicals such as superoxide, hydroxyl, and peroxyl radicals. It also inhibits lipid peroxidation and protects biomolecules like DNA and proteins from oxidative damage.
• Anti-inflammatory effects: It modulates inflammatory pathways by inhibiting enzymes like cyclooxygenase (COX) and lipoxygenase (LOX) and suppresses the release of pro-inflammatory cytokines such as TNF-α and IL-6.
• Cardioprotective effects: Quercetin supports cardiovascular health by improving endothelial function, reducing low-density lipoprotein (LDL) oxidation, and exerting antihypertensive effects through nitric oxide modulation.
• Anticancer potential: It influences multiple signalling pathways involved in carcinogenesis, including apoptosis induction, cell cycle arrest, and inhibition of angiogenesis and metastasis.
• Neuroprotective action: Quercetin crosses the blood–brain barrier and exhibits neuroprotective effects by reducing oxidative stress, inhibiting neuroinflammation, and promoting neuronal survival, which has implications in disorders such as Alzheimer’s and Parkinson’s disease.

These diverse activities underscore quercetin’s potential as a multifunctional therapeutic molecule for chronic disease prevention and treatment.[11,12]

Pharmacokinetic Limitations

Despite its remarkable pharmacological profile, quercetin’s therapeutic utility is limited by poor pharmacokinetics. Its aqueous solubility is extremely low, approximately 0.01 mg/mL, which leads to poor dissolution in gastrointestinal fluids and low intestinal permeability. Consequently, only a small fraction of orally administered quercetin is absorbed. Furthermore, once absorbed, quercetin undergoes extensive phase II metabolism, primarily through glucuronidation and sulfation in the intestinal mucosa and liver. These metabolic processes rapidly convert the active aglycone form into conjugated metabolites, which often have reduced biological activity.[13] In addition, quercetin exhibits a short biological half-life and rapid systemic clearance, resulting in limited plasma concentrations after oral administration. Its poor stability under physiological conditions further contributes to its degradation before reaching target tissues. These challenges collectively result in very low oral bioavailability, reported to be less than 20%, severely restricting its clinical applicability.[14]

Need for Bioavailability Enhancement

To unlock the full therapeutic potential of quercetin, it is essential to develop advanced delivery systems capable of overcoming these biopharmaceutical barriers. Strategies such as lipid-based carriers, polymeric nanoparticles, inclusion complexes, and phospholipid conjugates have been explored to improve solubility, permeability, and metabolic stability. Among these, phytosomes-phospholipid complexes that enhance lipophilicity and membrane compatibility, have demonstrated superior performance in enhancing quercetin’s absorption and bioavailability. These systems not only facilitate efficient transport across biological membranes but also protect quercetin from premature degradation, thereby maximizing its therapeutic efficacy.[15]

Table 1. Physicochemical and Pharmacological Properties of Quercetin

2. Phytosome Technology: Concept and Mechanism

Over the last decade, phytosome technology has emerged as an innovative and highly efficient delivery system for enhancing the bioavailability of plant-derived bioactives such as polyphenols, flavonoids, and terpenoids. The term “phytosome” is derived from the Greek words phyto (plant) and soma (body), indicating a natural complex formed between a plant constituent and a phospholipid molecule. This system overcomes the inherent solubility and permeability challenges of many phytochemicals by transforming them into lipid-compatible complexes capable of interacting effectively with biological membranes.[16]

Concept and Definition

A phytosome is defined as a molecular complex formed between a polar phytoconstituent and a phospholipid, most commonly phosphatidylcholine, at a molar ratio of 1:1 or 1:2. Unlike conventional liposomes, where the active compound is merely encapsulated within the vesicular structure, phytosomes involve a chemical association, typically through hydrogen bonding between the hydroxyl groups of the phytoconstituent and the polar head (phosphate and choline moiety) of the phospholipid. This interaction imparts amphiphilic characteristics to the complex, rendering it both hydrophilic and lipophilic. Consequently, the complex becomes more compatible with lipid-rich biological membranes, significantly improving its absorption, transport, and bioavailability.[17] Phosphatidylcholine plays a central role in phytosome formation. It consists of a glycerol backbone linked to two fatty acid chains and a phosphoric acid attached to a choline group. The hydrophilic head of phosphatidylcholine interacts with the polar functional groups of the bioactive compound, while the nonpolar tail aligns with lipid environments. This dual nature allows the phytosome complex to seamlessly integrate into cellular membranes, facilitating passive diffusion across biological barriers such as the intestinal epithelium.[18]

Mechanism of Phytosome Formation and Action

The mechanism of phytosome formation involves the establishment of hydrogen bonds between the polar functional groups, typically hydroxyl or carbonyl of the phytoconstituent and the polar head group of the phospholipid. When quercetin, for example, interacts with phosphatidylcholine, its multiple hydroxyl groups form stable hydrogen bonds with the phosphate and ammonium groups of the lipid molecule. This results in the formation of a discrete, stable complex that is not merely a mixture but a distinct chemical entity.[19] Once administered, the lipid-compatible phytosome complex exhibits enhanced membrane permeability and solubility. Its amphiphilic structure allows it to dissolve readily in both aqueous and lipid environments, thereby improving its dispersion in gastrointestinal fluids and facilitating passive diffusion through the lipid bilayer of enterocytes. This enhanced permeability enables higher systemic absorption of quercetin, while the phospholipid matrix provides protection against enzymatic degradation and oxidative damage during transit. Moreover, because phosphatidylcholine is a natural component of biological membranes, phytosomes exhibit excellent biocompatibility and low toxicity, further supporting their suitability for therapeutic applications.[20]

Preparation Methods

Several techniques have been developed for the preparation of phytosomes, each offering distinct advantages in terms of yield, particle size control, and scalability:

1. Solvent Evaporation Method

In this widely used technique, the phytoconstituent and phospholipid are dissolved in an organic solvent such as dichloromethane or ethanol. The solvent is then evaporated under reduced pressure to form a thin film, which is subsequently hydrated to yield the phytosome complex.

2. Anti-Solvent Precipitation Method

The phytoconstituent and phospholipid are first dissolved in a common organic solvent. Upon addition of a non-solvent such as water or n-hexane, the complex precipitates out, which can then be filtered and dried to obtain the phytosome.

3. Rotary Evaporation Technique

This method involves dissolving both components in a volatile organic solvent and evaporating the solvent under vacuum using a rotary evaporator. The resulting film is then collected and dried under nitrogen or in a desiccator.

4. Thin-Film Hydration Method

The phytoconstituent and phospholipid are co-dissolved and spread into a thin layer on the walls of a flask. After solvent evaporation, hydration with an aqueous buffer under controlled agitation produces vesicular phytosomes.

5. Supercritical Fluid Method

This advanced, solvent-free technique uses supercritical carbon dioxide as a medium for complex formation. It offers superior control over particle size, eliminates residual solvents, and yields highly pure phytosome formulations suitable for pharmaceutical use. Each of these methods can be optimized by adjusting parameters such as molar ratio, temperature, solvent type, and reaction time to maximize complexation efficiency and stability.[21,22]

Phytosomes vs. Liposomes

Although phytosomes and liposomes may appear similar in structure, they differ fundamentally in their composition and mechanism of action. In liposomes, the bioactive compound is physically encapsulated within the aqueous or lipid compartment of the vesicle, while in phytosomes, the phytoconstituent forms a chemical complex with the phospholipid molecule. This distinction results in several key advantages for phytosomes, including higher stability, better drug loading efficiency, and improved bioavailability.[23]

Table 2. Comparison of Phytosomes with Other Nanocarriers