Ultra-slow release of hydrophilic drugs via multilamellar-multivesicular liposomes formed by unsaturated phospholipids.

Maintaining therapeutic drug concentrations at a target site while limiting systemic exposure is difficult for hydrophilic drugs, which rapidly diffuse from the injection site. Liposomes are widely used carriers, yet designs based on rigid, saturated phospholipids aim to reduce membrane permeability but often yield modest loading and substantial burst release. Here we compared liposomes composed of phospholipids of identical chain length but varying unsaturation, prepared under matched conditions. Contrary to the expectation that unsaturation accelerates release, liposomes based on 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) showed approximately 3-fold higher loading, 11-fold lower initial release and 4-fold lower release at 7 days than saturated analogues. These effects correlated with the emergence of multilamellar and multivesicular structures and extended across diverse hydrophilic drugs. In a rat sciatic nerve block model, tetrodotoxin-loaded liposomes produced 2-3 weeks of blockade without systemic toxicity, establishing a simple platform for sustained local delivery.