Phytochemicals are naturally occurring compounds found in plants (from the Greek word “phyton” meaning plant) . These bioactive compounds are responsible for the color, flavor, and aroma of plants, but more importantly, they contribute to the plant’s defense mechanisms against pathogens, pests, and environmental stresses. Beyond their role in plant biology, phytochemicals have gained significant attention for their potential health benefits in humans . Although they are not essential nutrients like vitamins and minerals, phytochemicals play a crucial role in maintaining health and preventing disease. These compounds are broadly categorized into several classes, including alkaloids, flavonoids, phenolic acids, terpenoids, and glycosides, each with distinct chemical structures and biological activities .

Phytochemicals have captured the interest of the scientific community and the pharmaceutical industry alike because of their extensive therapeutic potential. They function as antioxidants, anti-inflammatory agents, anticancer compounds, and antimicrobials, offering a natural and multifaceted arsenal for combating a wide array of diseases . Despite their promising bioactivities, the clinical application of phytochemicals is often limited by several inherent drawbacks such as poor water solubility, low bioavailability, rapid metabolism, and instability under physiological conditions . These challenges necessitate the development of advanced delivery systems to harness the full potential of phytochemicals in therapeutic applications.

Polymer lipid hybrid nanoparticles (PLHNPs) represent an innovative class of delivery vehicles that combines the beneficial properties of both polymeric and lipid-based nanoparticles, thus offering a creative approach to enhance the delivery and efficacy of drugs/phytochemicals. The architecture of PLHNPs typically consists of a lipid core or shell enveloped by a polymer matrix, which can vary in its configuration depending on the specific requirements of the delivery system . The lipid components, often phospholipids, cholesterol, and surfactants are integral for solubilizing lipophilic drugs. The polymer component, which can include materials such as polyethylene glycol (PEG), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), and chitosan (CHS), provides structural integrity, controlled release properties, and protection against premature degradation . This hybrid structure improves the encapsulation efficiency of phytochemicals/drugs and enhances their solubility, stability, and bioavailability. Additionally, the physicochemical characteristics of PLHNPs can be tailored by varying the concentrations of polymers and lipids .

PLHNPs can address various challenges associated with phytochemical delivery. The benefits of PLHNPs include their small particle size, high encapsulation efficiency, enhanced stability, and improved dissolution in harsh gastrointestinal (GI) fluids. Following oral administration, PLHNPs demonstrate superior intestinal absorption and bioavailability, attributed to their enhanced stability and dissolution rate in GI fluids. Further, PLHNPs overcome limitations such as rapid metabolism and limited bioavailability by encapsulating phytochemicals within the hybrid matrices. This encapsulation enhances the stability of phytochemicals, extends their circulation time within the body, and enhances their therapeutic effectiveness . Additionally, PLHNPs possess the capability to encapsulate and co-deliver two drugs with distinct physicochemical characteristics to a targeted site and show synergistic therapeutic efficacy. In PLHNPs, the lipophilic drugs are encapsulated within the polymeric core, while hydrophilic drugs are entrapped in the lipid shell. PLHNPs demonstrate relatively greater loading capacity for lipophilic compounds than other nanoparticle systems .

Moreover, the surface modification of PLHNPs with targeting ligands, such as antibodies, peptides, or aptamers, has been explored to improve the selective delivery of drugs/phytochemicals to specific tissues or cells. A site-specific targeting approach enhances the therapeutic efficacy of phytochemicals and reduces systemic toxicity. In addition to enhancing solubility and targeting, PLHNPs offer controlled release properties that are crucial for maintaining therapeutic drug levels over extended periods of time . By adjusting the polymer composition and lipid matrix, researchers can fine-tune the release kinetics of phytochemicals, ensuring sustained therapeutic effects. This controlled release mechanism is particularly advantageous for chronic conditions requiring long-term treatment, such as cancer, cardiovascular diseases, and neurodegenerative disorders .

This review aims to discuss the ability of PLHNPs to improve the therapeutic delivery of phytochemicals for biomedical applications. In this review, we discuss the obstacles in the conventional delivery of phytochemicals, types of PLHNPs, different phytochemical-loaded PLHNPs for improved phytochemical delivery, challenges in clinical translation of PLHNPs, and future perspectives.

The conventional delivery of phytochemicals faces numerous challenges that limit its clinical application and therapeutic efficacy. These challenges arise from the physicochemical characteristics of phytochemicals, as well as from the physiological barriers they encounter in the body. One major challenge is poor water solubility. Many phytochemicals are hydrophobic and show poor water solubility, which significantly restricts their absorption in the gastrointestinal tract (GIT) when administered orally. This low solubility leads to low bioavailability, resulting in sub-therapeutic levels of the phytochemical at the target site . Another significant issue is low bioavailability. Bioavailability refers to the proportion of an administered substance that enters the bloodstream and is available for therapeutic action. Phytochemicals often exhibit low bioavailability due to poor solubility, rapid metabolism, and degradation in the physiological fluids. This necessitates higher doses to achieve therapeutic effects, which may increase the risk of side effects and toxicity . Chemical instability is also a critical challenge. Phytochemicals can be chemically unstable and degrade under physiological conditions, such as varying pH levels, temperature, and enzymatic activity. Degradation reduces the effective concentration of the phytochemical, diminishing its therapeutic potential . Rapid metabolism and clearance further complicate phytochemical delivery. Phytochemicals are often rapidly metabolized by liver enzymes and cleared from the body through renal or biliary excretion, resulting in short plasma half-lives and requiring frequent dosing to maintain effective therapeutic levels. This rapid clearance reduces the duration of action, making it challenging to achieve sustained therapeutic effects . Poor permeability and penetration are additional obstacles. Phytochemicals may have difficulties crossing biological membranes, such as the intestinal epithelium or the blood–brain barrier, because of their molecular size, polarity, or lipophilicity. Poor permeability limits the ability of phytochemicals to reach intracellular or central nervous system targets, reducing therapeutic efficacy in tissues that are difficult to access. Variability in absorption is another significant issue. The absorption of phytochemicals can be influenced by various factors, including food intake, gut microbiota, and individual genetic differences. This variability leads to inconsistent therapeutic outcomes among different individuals, and food–drug interactions can further complicate dosing regimens and efficacy . Further, conventional delivery methods often lack specificity, resulting in the distribution of phytochemicals throughout the body rather than targeting specific tissues or cells. Non-specific distribution increases the risk of off-target effects and systemic toxicity, reducing the concentration of the phytochemical at the desired site of action and decreasing therapeutic effectiveness . In addition, conventional delivery systems often cannot provide controlled or sustained release of phytochemicals, leading to fluctuating plasma levels. These fluctuations can result in suboptimal therapeutic effects and increased side effects. Lack of controlled release is particularly problematic for chronic conditions that require consistent drug exposure over extended periods of time . Therefore, there is a need for innovative delivery systems that improve solubility, stability, bioavailability, and targeted delivery, while also providing controlled release. PLHNPs represent a promising solution to many of these challenges, offering a versatile platform to maximize the therapeutic potential of phytochemicals.

PLHNPs represent an innovative solution for the effective delivery of phytochemicals by harnessing the combined advantages of both polymeric and lipidic nanoparticles. PLHNPs represent higher encapsulation efficiency, ensuring that a higher proportion of the phytochemical payload is successfully encapsulated within the hybrid matrix of nanoparticles . This improved encapsulation leads to enhanced bioavailability, meaning more of the phytochemical can reach the systemic circulation, resulting in greater therapeutic efficacy. Structurally, PLHNPs maintain their integrity through a unique hybrid architecture. They typically consist of a lipid core or shell surrounded by a polymer matrix. The lipid components, including phospholipids, cholesterol, and surfactants, play a crucial role in solubilizing lipophilic phytochemicals and facilitating interactions with biological membranes. The polymers provide structural stability, controlled release properties, and protection against premature degradation . PLHNPs address various challenges associated with phytochemical delivery. They overcome limitations such as poor solubility, rapid metabolism, and limited bioavailability by encapsulating phytochemicals within lipid–polymer hybrid matrices. This encapsulation enhances the stability of phytochemicals, prolongs their circulation time in the body, and enhances their therapeutic effectiveness . Additionally, surface engineering of PLHNPs with different ligands facilitates specific delivery of drug/phytochemicals to desired tissues or cells, reduces their adverse effects, and improves their therapeutic efficacy . The development of PLHNPs for phytochemical delivery holds significant promise across various biomedical applications. PLHNPs can be utilized in cancer therapy, cardiovascular disease management, neurodegenerative disorder treatment, and other areas of medicine where phytochemicals show therapeutic potential.

As the name suggests, polymer core–lipid shell hybrid nanoparticles are composed of a polymer core that is covered by mono/bilayers of a lipoidal shell. The polymeric core significantly enhances the stability of the outer lipoidal shell. The biodegradable polymeric core with a stable outer lipoidal shell makes these PLHNPs an excellent nanocarrier for therapeutic drug delivery and the treatment of various diseases. The amphiphilicity of biodegradable polymers and lipids promotes the encapsulation of both lipophilic as well as hydrophilic chemotherapeutic drugs within the hybrid system. During the development of LPHNPs, different physicochemical characteristics such as size, loading capacity, charge, solubility, release, and colloidal stability can be modulated by modification in the polymer/lipid ratio .

Monolithic PLHNPs are the simplest among PLHNPs; they are simply mixed nanosystems of polymer/copolymer and lipids with the help of surfactants. In this system, the lipids are scattered in a polymeric/copolymeric matrix . Monolithic PLHNP systems are very similar to colloidal polymeric nanocarriers. In these nanocarriers, phospholipids help to form a carrier-like structure, which is an integral part of the system. In addition, the modification of lipoidal layers with a PEG chain provides flexibility to the nanocarrier. The ratio of the polymer and lipid can easily be adjusted to modulate the physicochemical characteristics of the nanocarrier and can reduce systemic toxicity .

The core–shell type hollow PLHNPs comprise an inner hollow positively charged lipidic core, a polymeric layer in the middle, and an outer PEG lipoidal layer . The inner hollow core of the system is filled with water/or buffer. Because of the positive charge, the lipids in the inner core encapsulate the drug more efficiently compared to PLHNPs with a polymeric core. In addition, because of the outer lipoidal PEG layer, these nanocarriers escape the uptake by macrophages and enhance the stability of the biological fluids . During the development of these nanocarriers, the concentration of cationic lipids for the inner core, density of the PEG chain on the outer layer, and molecular weight of the polymers are adjusted to modulate their physicochemical characteristics .

As the name suggests, the structural arrangement of these nanocarriers involves the surface coating of liposomes with biodegradable polymers/copolymers. The surface modification not only imparts surface functionality to the nanocarrier but also enhances its therapeutic efficacy by site-specific targeting and controlled release of the encapsulated drugs. Among all PLHNPs, these hybrid nanocarriers show the highest stability in the biological fluids and stimuli-responsive release of encapsulated drugs. In addition, the polymeric cage protects the drug from the harsh environment, and encapsulated drugs can be released under specific biological conditions. Further, the polymer coating provides better colloidal stability, sustained drug release, and high loading capacity to the hybrid nanocarriers .

PLHNPs have been coated with cell membranes (e.g., erythrocytes) to develop membrane-camouflaged PLHNPs. These hybrid nanocarriers are also called biomimetic hybrid nanocarriers because their surface chemistry mimics natural cell membranes . The PLHNPs are coated with cell membranes via the extrusion technique. The coating of PLHNPs with red blood cells yields a natural vehicle for drug delivery, and these nanocarriers can easily escape the uptake by macrophages. In this system, the drugs are encapsulated in the lipophilic polymeric core, and the lipids in the outer natural membrane enhance the sustained release of drugs. With the development of these hybrid nanocarriers, the biological barriers in therapeutic drug delivery can be easily overcome. These hybrid nanocarriers show prolonged half-life and stability in biological systems, thereby enhancing therapeutic efficacy .

Figure 5: Image illustrating the chemical structures of different phytochemicals reviewed in this paper for therapeutic delivery with PLHNPs for the treatment of different diseases.

Table 1: Summary of pharmaceutical properties with major findings of different phytochemical encapsulated PLHNPs.