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, H