Liposomes have been extensively used in the pharmaceutical and cosmetic industries as an effective way of delivering bioactive compounds and more recently in the food industry to explore their ability in delivering flavors, nutrients, and antimicrobial compounds. The major drawbacks related to the conventional liposome production methods is the use of toxic organic solvents during fabrication; and when unsaturated phosphatidylcholines (PC) are used as liposome’s bilayer constituent materials, synthesized liposomes are not stable at elevated temperatures (> 60 oC), which limits their use in food systems. Thus, there exists an unmet need for the development of a safe and scalable method for liposome synthesis, and the potential of synthesized liposomes to maintain structural integrity during high temperature treatments. To address the first problem, we used a supercritical carbon dioxide (SC-CO2) based novel and environmentally benign semi-continuous process for liposome synthesis; which involves rapid expansion of supercritical solution using a venturi-based system (Vent-RESS) based on Bernoulli’s principle. The process optimization was conducted by experimentally determining equilibrium-solubility of PC in SC-CO2, followed by developing predictive-models for PC’s solubility by using different cubic equations of state. Inspired by the heat stability of milk fat globules and the thermotropic nature of milk fat globule membrane (MFGM), we postulated that liposomes synthesized from MFGM phospholipids could be heat-stable. Vent-RESS system was used to generate multi-vitamin loaded liposomes from a cocktail of MFGM phospholipids, supercritically extracted from buttermilk powder; and synthesized liposomes retained their bilayer structure even when heated at 90 oC. However, these liposomes were still not suitable for oral delivery applications owing to the susceptibility of liposomal phospholipid bilayer membrane towards acidic and enzymatic degradation in stomach. Thus, synthesized multi-vitamin loaded liposomes were enterically coated with two different pH-responsive, biocompatible, and nontoxic coatings (i.e., dual layer of β-lactoglobulin and chitosan or Eudragit® S100) to facilitate simultaneous site-specific delivery of encapsulated hydrophilic and lipophilic bioactives. The enteric coating enabled the protection of the encapsulated payload against the deleterious gastric environment and subsequent delivery in the in vitro simulated intestinal condition. This method offers an attractive scalable approach for fortification and targeted delivery of bioactives via foods and beverages.