Abstract
Omega-3 and omega-6 fatty acids play essential roles in human health, being widely used in the prevention and treatment of various conditions, such as cardiovascular diseases, inflammation, and metabolic disorders. However, their oral administration faces significant challenges, including low solubility, rapid oxidation, and low bioavailability, which limit their therapeutic efficacy. This article explores recent advances in oral drug delivery systems designed for polyunsaturated fatty acids, highlighting how innovative technologies, such as nanoemulsions, liposomes, microencapsulation, and solid lipid nanoparticles (SLNs/NLCs), can improve their stability, absorption and clinical performance.
Most commonly used processes to prepare liposomes. (A) Lipid film hydration; (B) Ethanol injection; (C) Sonication, with sonicator or ultrasonic bath; (D) Extrusion, with an extruder apparatus.Arrows indicate the flow of lipid vesicles through the membrane during extrusion.
In addition, the main natural sources of these compounds, as well as their extraction and purification methods, and the challenges related to their absorption and metabolism are discussed. This narrative review was based mainly on a comprehensive search of peer-reviewed literature published between 2015 and 2025 in PubMed, Scopus, and Web of Science. The therapeutic benefits of these emerging approaches are analyzed by comparing conventional methods with modern delivery strategies to optimize the use of omega-3 and omega-6 in the body.
Finally, the article outlines future perspectives and regulatory challenges associated with these technologies, highlighting their potential to revolutionize the administration of essential fatty acids and broaden their applications in medicine and nutrition.
Introduction
Among the macronutrients in diets, lipids account for approximately 25–45% of the total calories of the diet of humans in occidental countries, with their main sources being vegetable oils and animal fats [1,2,3]. Fatty acids are structural constituents of lipids, consisting of linear hydrocarbons that contain between four and thirty-six carbon atoms and a terminal carboxyl (-COOH) functional group. Carbon chains may contain only single bonds (saturated fatty acids, SFA), one double bond (monounsaturated fatty acids, MUFA n-9 or n-7), or multiple double bonds (polyunsaturated fatty acids, PUFAs). PUFAs are particularly relevant from both nutritional and therapeutic perspectives, and their classification in different families (n-3 and n-6) is based on the position of the first unsaturation from the methyl end of the molecule [4,5,6].
Long-chain polyunsaturated fatty acids (LC-PUFAs) comprise molecules with 20 or more carbon atoms and two or more unsaturations, playing essential roles in the maintenance of cellular homeostasis, inflammatory modulation, and neurodevelopment [6,7]. The main families of LC-PUFAs include the omega-3 fatty acids (n-3) and omega-6 (n-6), which differ by the location of the first double bond at the third or sixth carbon, respectively. The n-3 PUFAs are metabolic derivatives of alpha-linolenic acid (ALA; 18:3n-3), that is converted into eicosapentanoic acid (EPA; 20:5n-3), and docosahexaenoic acid (DHA; 22:6n-3), both recognized for their anti-inflammatory, anticancer, cardioprotective, and neuroprotective properties [6,8,9,10]. Meanwhile, n-6 PUFAs are derived from linoleic acid (LA; 18:2n-6), whose endogenous conversion results in the formation of arachidonic acid (ARA; 20:4n-6), a precursor of pro-inflammatory eicosanoids [11,12].
(A) Microencapsulation process via spray drying; (B) General process of coacervation for microencapsulation; (C) Microcapsule structures that can be generated by spray drying and coacervation, (I) matrix particles; (II) core–shell structures; (III) multicore or polynuclear capsules; (IV) empty core (vacuolated) capsules.
Dietary sources vary significantly in fatty acids composition: marine oils, such as fish oil, are rich in LC-PUFA of the n-3 family, whereas vegetable oils, such as soybean and corn oils, contain high levels of n-6 PUFAs [13,14]. An imbalance in the intake between these two families, particularly an increased n-6/n-3 ratio, has been associated with unfavorable metabolic outcomes, highlighting the importance of dietary strategies and technologies that promote a more balanced intake of these essential nutrients [11,15,16,17].
LC-PUFAs play essential roles in human health by contributing to the integrity of cellular membranes, the regulation of inflammation, neuromuscular development, cardiovascular function, and energy metabolism [5,18,19,20,21,22,23]. Scientific evidence also highlights their preventive and therapeutic effects, underscoring their relevance to contemporary nutrition and pharmacology [11,24,25,26,27,28,29].
Despite the well-recognized benefits, the oral administration of these fatty acids faces significant challenges that compromise their therapeutic effectiveness. Low solubility in aqueous media, combined with high susceptibility to lipid oxidation, results in chemical instability during storage and gastrointestinal transit [30,31,32]. These factors, combined with limited absorption and extensive first-pass metabolism, result in low systemic bioavailability, thereby restricting the achievement of optimal biological efficacy [30,33].
In light of these limitations, the development of controlled-release systems emerges as a valuable strategy to optimize the delivery and efficacy of LC-PUFAs. These technologies aim to protect the compounds from degradation, improve their solubilization, and promote modulated and targeted release, enhancing absorption and reducing adverse effects. Therefore, advanced oral delivery systems represent an innovative approach to improve the therapeutic impacts of natural fatty acids, responding to current demands on functional nutrition and pharmacotherapy.
In this review, we critically examine these delivery systems, highlighting their design, functionality, and potential to enhance the bioavailability and efficacy of natural polyunsaturated fatty acids. The literature search was conducted in databases including Web of Science, Scopus, and PubMed, with a focus on peer-reviewed studies published between 2015 and 2025. Earlier seminal publications were also considered when necessary to contextualize the discussion. Data extracted from the selected studies were qualitatively analyzed and organized according to the type of delivery system, formulation strategy, physicochemical properties, and reported biological or therapeutic effects. This qualitative synthesis allowed the identification of converging evidence, technological trends, and research gaps in the field.
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Zazula, M.F.; Pozzan, R.; dos Reis, G.A.; Maciel, M.; Horlem, T.; Banckes, T.N.; Pereira, J.L.S.; Sales-Campos, C.; Fernandes, L.C.; Martinez-Burgos, W.J.; et al. Advances in Oral Drug Delivery Systems for Natural Polyunsaturated Fatty Acids: Enhancing Bioavailability and Therapeutic Potential. Pharmaceutics 2025, 17, 1377. https://doi.org/10.3390/pharmaceutics17111377
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