Phytosomal Delivery of Natural Bioactives: Advancing Bioavailability, Targeted Drug Delivery, and Clinical Translation

Natural bioactive compounds, especially plant-derived phytoconstituents, have gained significant interest due to their structural diversity, multitarget pharmacological activities, and favourable safety profiles. Their pharmaceutical translation is often hindered by poor aqueous solubility, limited membrane permeability, chemical instability, extensive first-pass metabolism, and, therefore, low oral bioavailability. Phytosomes, which are molecular complexes of bioactive compounds with phospholipids, have emerged as a new, effective, lipid-based delivery platform that can overcome these biopharmaceutical limitations and improve solubility, membrane interactions, systemic exposure, and therapeutic efficacy. The present review critically analyses recent advancements in phytosomal drug delivery, from formulation development to clinical translation, focusing on molecular complexation mechanisms, formulation strategies, physicochemical characterisation, pharmacokinetic enhancement, therapeutic applications, and challenges in clinical translation. The current review combines pharmaceutical design principles with recent advances in quality-by-design (QbD), computational formulation optimisation, hybrid phytosomal systems, scalable manufacturing approaches, and targeted delivery strategies. In addition, prospects for the future extension of phospholipid complexation to bioactive compounds from marine organisms, fungi, microorganisms, and algae are discussed in relevance to the next-generation natural product therapeutics. The present review serves as an emerging link between the discovery of natural bioactive compounds and the development of clinically translatable phytosomal systems from a pharmaceutical perspective.