Abstract

This study reports the development of a novel liposomal delivery system in which red palm oil (RPO) was co-encapsulated with curcumin (CC) pre-solubilized in a natural deep eutectic solvent (NADES-CC), designed to enhance the stability and bioavailability of lipophilic bioactive compounds. Liposomes (LP) were fabricated using thin-film hydration. Blank (empty) LP (Empty-LP), NADES-CC-loaded LP (CC-LP), RPO-loaded LP (RPO-LP), and co-encapsulated formulations (CP1-LP, CP2-LP, and CP3-LP; NADES-CC/RPO ratios of 1:3, 1:1, and 3:1, respectively) were produced using the same protocol and systematically characterized in terms of encapsulation efficiency (EE), morphology, antioxidant activity, and in vitro digestion behavior. The optimized formulation, CP2-LP, exhibited a markedly higher EE for β-carotene (80.02%) compared with RPO-LP (58.14%) and retained moderate levels of CC (~ 50 to 60%) throughout 240 min of simulated gastrointestinal (GI) digestion. Transmission electron microscopy revealed typical vesicular morphology with improved structural stability. Co-encapsulation significantly retarded lipid hydrolysis, lowered free fatty acid release, and preserved antioxidant activity during both storage and digestion. Moreover, CP2-LP and CP3-LP maintained superior radical-scavenging capacity over 30 days and exhibited good macrophage compatibility and nitric oxide inhibitory effects in RAW264.7 cells. After 30 days of storage, these co-encapsulated formulations retained 62.39–76.23% of their initial DPPH radical scavenging activity, whereas CC-LP and RPO-LP retained only 23.08–27.65% and Empty-LP showed negligible activity. Collectively, these findings highlight the synergistic role of NADES-CC and RPO in enhancing liposomal stability and delivery efficiency, as reflected by sustained CC retention and improved bioaccessibility, offering a promising platform for nutraceutical applications under GI conditions.