Supercritical CO₂ engineered niosomes as functional materials for oral drug delivery

Achieving scalable and controlled production of nanovesicles remains a major bottleneck in translating nanocarrier systems to industry. Conventional batch methods, such as thin-film hydration and ethanol injection, often show low reproducibility, residual solvents, and multistep workflows that hinder scale-up. To address these challenges, we developed SuperSomes, a supercritical CO₂ (SC-CO₂)-based process enabling continuous, solvent-free fabrication of nanovesicles. The method relies on atomization of an aqueous phase within a gas-expanded medium, promoting rapid self-assembly of surfactant or lipid molecules under mild conditions and allowing precise control over vesicle size and composition. As a proof of concept, we used SuperSomes to generate Span 80/Tween 80 or Span 80/Capric acid (C10) niosomes for oral drug delivery. By systematically tuning surfactant ratios, we identified how hydrophilic-lipophilic balance and packing parameters govern vesicle formation and stability. The resulting niosomes showed high resistance to pH and temperature variations. In vitro Caco-2 studies revealed enhanced intracellular uptake and paracellular transport, indicating a dual absorption mechanism. In vivo, orally administered fluorescent niosomes exhibited minimal gastric retention and improved intestinal permeation. Overall, SuperSomes offers a reproducible, scalable, and environmentally friendly platform for producing nanocarriers tailored for oral delivery, overcoming key limitations of conventional manufacturing approaches.