Tomato processing by-products represent a sustainable source of antioxidant bioactives, but their use as functional ingredients requires formulation strategies able to improve their stability and oral delivery. In this study, a hydroethanolic tomato by-product extract, rich in carotenoids (β-carotene, phytoene and lycopene) and phenolic compounds (mainly quercetin-3-galactoside), was incorporated into phospholipid-based vesicles prepared by an organic solvent-free direct sonication method. Both liposomes and nutriosomes exhibited nanometric size (<100 nm), low polydispersity index (∼0.213), a highly negative surface charge (∼−43 mV). Both systems retained more than 75% of their initial antioxidant activity after dialysis and showed good physicochemical stability during 180 days of storage at 4 °C. Under simulated salivary, gastric and intestinal pH and ionic conditions, both formulations maintained their colloidal stability. However, nutriosomes showed superior technological performance following freeze-drying and rehydration, displaying only a limited increase in particle size while preserving a narrow size distribution. In Caco-2 cells, all formulations were biocompatible, maintaining cell viability above 90% after 48 h. Under oxidative stress conditions, free extract and liposomes failed to significantly counteract hydrogen peroxide-induced cytotoxicity, whereas nutriosomes restored cell viability to approximately 93%. Owing to their superior technological and biological performance, nutriosomes were successfully incorporated into gummy formulations, which completely dissolved under simulated gastric conditions while releasing vesicles that retained their nanoscale characteristics, with a mean diameter of ∼249 nm and a polydispersity index of ∼0.211. Overall, these findings demonstrate that nutriosomes effectively enhance both the processing stability and biological efficacy of tomato by-product phytocomplexes, supporting their development as sustainable functional ingredients for gummy-based oral nutraceuticals.
