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This study was aimed to develop a novel nanocarrier for coenzyme Q10 (CoQ10) by a green process that prevented the use of surfactants and organic solvents. Triglyceride/phospholipid‐based nanocarriers were developed through high‐pressure homogenization (an industrial feasible process), and a 25‐1 fractional factorial design was adopted to assess the influences of formulation variables on the considered responses, including vesicle size, entrapment efficiency, loading capacity, and solubility of the vehicles in simulated gastrointestinal fluids. The optimized formulation was further in‐depth characterized in terms of morphology, release behavior, biocompatibility (Caco‐2 cell cytotoxicity and histological examination), thermal behavior, and Fourier transform infrared analysis. Optimal nanocarriers were found to have mean particle size of 75 nm, narrow particle distribution, and CoQ10 entrapment of 95%. The optimized formulation was stable upon incubation in simulated gastrointestinal fluids without considerable leakage of cargo, which was in agreement with their sustained release behavior. Microscopic observations also confirmed nanosized nature of the vesicles and revealed their spherical shape. Moreover, toxicity evaluations at the cellular and tissue levels revealed their nontoxic nature. In conclusion, triglyceride/phospholipid‐based nanocarriers proved to be a green safe vehicle for delivery of CoQ10 with industrial‐scale production capability and could provide a new horizon for delivery of hydrophobic nutraceuticals. Practical application Green nanostructure formulation approaches have recently gained tremendous attraction for their safe profile especially when it comes to supplements, which are generally recommended for daily use. However, their sufficient association with cargoes and industrial‐scale production have remained considerable challenges. This study focuses on the development of lipid‐based nanocarriers for CoQ10 by an industrial feasible process that prevents the use of any surfactants or organic solvents.

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