Abstract
Nutraceuticals such as curcumin, resveratrol, lycopene, lutein, and coenzyme Q10 possess strong antioxidant and anti-inflammatory activities but their practical use is hindered by poor solubility and bioavailability. Traditional nanocarriers like liposomes, nanoemulsions, and polymeric nanoparticles often rely on surfactants and synthetic organic solvents that limit safety, scalability, and regulatory acceptance. The present study evaluated the Facilitated Self-Assembling Technology (FAST) platform as a clean-label alternative for generating bioavailable nutraceutical nanoparticles. Using only foodgrade facilitating medium, FAST enabled spontaneous formation of stable, amorphous nanoparticles with strong negative surface charge and high colloidal stability. Hybrid nanoparticles combining epigallocatechin-3-gallate-palmitates (EC16), curcumin, and resveratrol further improved surface charge, reduced size range, and exhibited enhanced stability under simulated gastric conditions. All formulations demonstrated excellent biocompatibility in XTT assays, with no reduction in viability compared to control. Fluorescent imaging of EC16/Cy5 fluorescent hybrid nanoparticles confirmed nanoparticle cell surface interactions without cytotoxicity. Compared with chemical conjugation and lipid-based nanoencapsulation, FAST offered faster, surfactant-free, and energy-efficient production, fully compliant with FDA generally recognized as safe (GRAS) standards. These results support the FAST platform as an efficient, economical, and scalable nanotechnology for next-generation functional beverages and oral nutraceutical delivery systems that meet both regulatory and consumer demands for natural, sustainable innovation.
Introduction
Nutraceuticals, defined as biologically active compounds derived from foods or botanical sources, have become a cornerstone of modern preventive medicine, offering diverse health benefits ranging from antioxidant, anticancer, and anti-inflammatory protection to neuro- and cardiometabolic support [1–3]. Nutraceuticals are differentiated from nutrients by providing therapeutic or prophylactic benefits beyond basic nutrition. Epidemiological and clinical studies consistently demonstrate that diets rich in bioactive phytochemicals correlate with reduced risk of cardiovascular disease, metabolic syndrome, cancer, and neurodegenerative disorders [1–4]. Driven by consumer awareness of wellness and the shift from treatment to prevention, the global nutraceutical market exceeded USD 540 billion in 2022 and is projected to surpass USD 1 trillion by 2030 [3–5]. Among the many studied bioactives, epigallocatechin-3-gallate (EGCG), curcumin, resveratrol, lycopene, lutein, and coenzyme Q10 (CoQ10) are particularly notable for their antioxidant, anti-inflammatory, and signaling-modulatory effects [5–10].
However, many nutraceuticals are hydrophobic, and the practical application of most lipophilic nutraceuticals, such as curcumin, resveratrol, lycopene, lutein, and coenzyme Q10 (CoQ10), is hindered by physicochemical and pharmacokinetic limitations, including poor aqueous solubility, rapid metabolism, and instability under physiological condition, resulting in limited intestinal absorption following oral consumption and rapid systemic clearance.
Curcumin in its native form, for example, yields plasma concentrations below 50 ng/mL even after gram-level doses, because of rapid metabolism [11–14]. Resveratrol exhibits high intestinal absorption but <1 % systemic bioavailability due to first-pass metabolism [6–8]. Lycopene typically achieves Cₘₐₓ values of only 0.6–1.2 μM [15,16], while lutein and CoQ10 remain in the nanomolar range even after supplementation [17–21]. Consequently, striking in-vitro efficacy seldom translates in vivo, underscoring the need for formulations that enhance solubility, stability, and permeability.
Recently, nanotechnology has emerged as a transformative approach for improving the pharmacokinetics and functionality of nutraceuticals, and nanoscale delivery systems now underpin many strategies to enhance dispersion, stability, and uptake of hydrophobic active biologics. These systems provide a larger surface area and improved protection against degradation, extending biological residence time and increasing absorption [22–24]. Various nano systems—including solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), liposomes, and nanoemulsions—have been widely explored to increase dispersion, protect against degradation, and promote absorption.
SLNs are composed of solid lipid matrices that encapsulate lipophilic compounds and enable controlled release; they are fabricated through hot or cold high-pressure homogenization, ultrasonication, or microemulsion techniques [4,22,23]. NLCs combine solid and liquid lipids to increase drug loading and minimize expulsion during crystallization [24]. Liposomes, formed from phospholipid bilayers, can entrap both hydrophilic and hydrophobic compounds and are typically produced by thin-film hydration, reverse-phase evaporation, ethanol injection, or lipid-film rehydration [22]. Nanoemulsions—surfactant-stabilized oil-in-water dispersions—are obtained via high-speed shearing, ultrasonication, phase-inversion temperature, or high-pressure homogenization [22,25]. Collectively these approaches have advanced nutraceutical delivery by several orders of magnitude, enabling inclusion of otherwise insoluble active ingredients in food, beverages, and supplements.
Nevertheless, conventional nanotechnologies rely heavily on synthetic surfactants and organic solvents, and therefore suffer from inherent weaknesses that constrain large-scale, food-grade deployment. Their dependence on synthetic surfactants (e.g., polysorbates, Spans, sodium dodecyl sulfate) and organic solvents (i.e. acetone, chloroform) introduces potential toxicity, irritancy, and environmental concerns [4,22,23]. Certain solvent residues are incompatible with “clean-label” expectations and may violate regulatory limits. Energy-intensive manufacturing processes such as ultrasonication and high-pressure homogenization can also degrade heat- or oxidation-sensitive nutraceuticals, lowering bioactivity. Stability remains another major issue: SLNs and NLCs undergo polymorphic transitions and aggregation, liposomes require precise lipid ratios and hydration
control, and nanoemulsions experience Ostwald ripening and phase separation. These complications could shorten shelf life and inflate production costs. From a regulatory perspective, agencies such as the Food and Drug Administration (FDA) and European Food Safety Authority (EFSA) require dedicated safety assessments and explicit labeling of engineered nanomaterials, limiting commercial acceptance of systems employing non-GRAS excipients [1,3].
Recognizing these obstacles, researchers have sought greener and simpler nanotechnologies employing fully food-grade materials. The Facilitated Self-Assembling Technology (FAST) platform represents one such innovation [26]. FAST is a surfactant-free nanotechnology that enables spontaneous formation of nanoscale complexes (i.e. micelles) entirely from Generally Recognized As Safe (GRAS) material. Through finely balanced non-covalent interactions such as hydrogen bonding, hydrophobic association, and van der Waals forces, FAST promotes molecular self-organization in liquid media under mild conditions. Unlike conventional systems that demand mechanical energy or surfactants, FAST relies on intrinsic amphiphilicity and charge distribution of its components to drive assembly into uniform nanoparticles typically ranging between 50–200 nm in diameter.
This self-assembly is conceptually analogous to micelle formation yet proceeds without surfactants or significant external energy. The resulting nanoparticles possess narrow size distribution and remarkable colloidal stability, making them well suited for nutraceutical, cosmetic, and pharmaceutical use. As the process occurs entirely in a liquid environment and all constituents are food-grade, the platform eliminates the toxicological and environmental concerns associated with traditional nanocarriers.
Figure 1 illustrates the self-assembly mechanism of the FAST process, in which amphiphilic nutraceutical molecules and GRAS material(s) interact via hydrophobic and hydrogen-bonding forces to form nanoscale particle/micelle structures under liquid, surfactant-free conditions. The pathway involves initial molecular association, nucleation of nanoclusters, and spontaneous growth into stable particles without high-energy input. This gentle, economical yet efficient mechanism preserves bioactivity and allows reproducible large-scale production using simple mixing steps under either isothermal or polythermal conditions.
We hypothesize that the FAST platform provides a safe, economical, and efficient method for converting nutraceutical compounds into aqueous-miscible, bioavailable nanoparticles with broad application. In this study, we evaluated the suitability of FAST-generated nanoparticles prepared from widely studied nutraceuticals—including EC16, curcumin, resveratrol, lycopene, lutein, and CoQ10—and their hybrid formulations for potential oral delivery. The nanoparticles were characterized for particle size, density, surface charge (zeta potential), crystalline structure, cytotoxicity, stability under acidic conditions, and cellular interaction by fluorescent imaging.
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Cai, J.; Dudish, C.; Mouna, A.; Jacob, A.; James, W.; Dickinson, D.; Yu, H.; Liu, Y.; Sarker, A. K.; Culha, M.; Garrepally, D.; Kittaka, M.; Hsu, S. Clean-Label and Food-Grade Preparation of Nutraceutical Nanoparticles Using Facilitated Self-Assembling Technology (FAST) for Functional Beverages. Preprints 2025, 2025120584. https://doi.org/10.20944/preprints202512.0584.v1
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