Interfacial Modulation of Cochleate Assembly via Cationic Surfactant Enables Enhanced Encapsulation of Water-Soluble Drugs

Cochleates offer a structurally robust lipid-based platform for drug delivery but remain limited by structural heterogeneity, aggregation, and poor encapsulation of water-soluble therapeutics due to weak bilayer partitioning. Here, we introduce a cationic surfactant-mediated interfacial engineering strategy to modulate cochleate assembly and enhance encapsulation of water-soluble drugs. Using cetyltrimethylammonium bromide (CTAB) as a model cationic surfactant and 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS) as the anionic lipid matrix, we demonstrate controlled modulation of bilayer electrostatics and lamellar organization during Ca²⁺-driven cochleate formation. Multimodal characterization using cryo-TEM, FE-SEM, SAXS, FTIR, and DSC indicates that CTAB incorporation occurs in a manner consistent with interfacial bilayer association, without disrupting Ca²⁺-bridged lamellar architecture, preserving the fundamental lamellar repeat spacing while systematically modulating lamellar coherence and colloidal stability. Using irinotecan as a mechanistically stringent model drug with limited intrinsic bilayer affinity, based on its amphiphilic, weakly basic nature and poor loading in unmodified cochleates, CTAB-engineered cochleates exhibit a marked increase in encapsulation efficiency and drug loading, together with improved structural integrity and sustained release under simulated gastrointestinal conditions. These enhancements arise from interactions that favor drug association at the bilayer-aqueous interface rather than deep hydrophobic partitioning, while maintaining cochleate structural organization. This work establishes interfacial electrostatic modulation as an important design principle for cochleate engineering, enabling efficient encapsulation and controlled release of water-soluble therapeutics without compromising structural integrity.