Escaping The Topical Trap: Reengineering Ufasomes for Smart Systemic Delivery

The transition from conventional dosage forms to targeted nanovesicular drug delivery systems has resulted in improved therapeutic efficacy and reduced systemic adverse effects. Ufasomes, a suspension of closed lipid bilayers of unsaturated fatty acids and their ionized species, have proven to be a promising alternative for conventional vesicular carrier systems, which address numerous drawbacks of liposomes, including high production costs, physical instability, and oxidative vulnerabilities. Ufasomes exhibit a fusogenic tendency that promotes deep fusion with the lipid bilayers of the skin due to their distinct pH-dependent stability. Hence, they are considered as an excellent vehicles for topical and transdermal drug delivery systems that provide a localized and sustained release of both lipophilic and hydrophilic drugs. Although switching to continuous microfluidic assembly is still a crucial manufacturing frontier, conventional techniques like thin-film hydration, reverse-phase evaporation, and ethanol injection methods are used for the preparation of ufasomes. This review assesses the structural dynamics, formulation parameters, and current manufacturing bottlenecks of ufasomes, emphasizing the importance of overcoming current systemic delivery limitations, specifically acidic degradation in the stomach, and investigates their emerging therapeutic applications in dermal oncology, dual-drug co-delivery, and AI-optimized precision medicine.