De Novo Lipid Switch Design for Reactive Oxygen Species-Triggered Liposomal Release

Liposomal nanocarriers are highly effective for drug delivery, since they shield encapsulated therapeutic cargo and enhance cellular infiltration. However, a drawback of liposomal carriers involves the limited release of contents after delivery. As such, stimulus-responsive liposomes harnessing synthetic lipid switches that trigger cargo release upon encountering disease-associated conditions have the potential to address this issue. Reactive oxygen species (ROS) have emerged as prominent target stimuli because of their upregulation in diseased cells. Lipid switches designed for liposome release are often derived from phospholipid precursors, an approach that suffers from high expense and hinders scalability because of the limited availability of phospholipids. To address this issue, we report the design and synthesis of an ROS-responsive lipid switch from first principles that does not utilize phospholipid precursors. This culminated in a scalable nonphospholipid switch that forms stable liposomes yet undergoes clean, H₂O₂-triggered degradation under aqueous oxidative conditions. Using Nile Red release, ANTS-DPX dequenching, and dynamic light scattering (DLS) experiments, we show that liposomes containing lipid switch 4 exhibit minimal basal leakage and maintain structural integrity, while H₂O₂ induces dose-dependent membrane permeabilization with characteristic changes in vesicle size. We also show that liposomes containing 4 demonstrate superior and more consistent results compared with those containing 6, which have longer acyl chains. PC-only negative controls display no comparable response, confirming that release arises from selective boronate oxidation rather than nonspecific degradation. These results highlight the potential of a synthetically accessible, modular nonphospholipid architecture for stimulus-responsive triggered release as a practical platform for redox-responsive therapeutic delivery.