Matheus Felipe Zazula, Roberta Pozzan, Guilherme Anacleto dos Reis, Mônica Maciel, Thomas Horlem, Tayná Nery Banckes, Josilene Lima Serra, Ceci Sales-Campos, Luiz Cláudio Fernandes, Walter José Martínez-Burgos, Katya Naliwaiko
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. 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.