Cardiovascular diseases are the world’s number one killer, causing 43% of all deaths and costing the EU 192 billion Euros annually. Delaying their progression using e.g. targeted drug delivery to atherosclerotic plaques is a number one priority in modern healthcare.The enzyme sphingomyelinase (SMase) is upregulated in atherosclerotic plaques. In vivo, dysregulation of enzymatic conversion of the cell membrane phospholipid sphingomyelin (SM) to ceramide by SMase leads to a change in ceramide concentration. This causes endothelial dysfunction, atherosclerosis, ischemic heart disease, emphysema, cancers, cystic fibrosis and depression. SMase-targeting drugs are an emerging research topic but no localised delivery vectors to alleviate negative systemic side effects are yet reported. This project marks two world-firsts: SMase as a target for drug delivery, and a liposome formulation from which release is not only targeted but ENDOGENOUSLY TRIGGERED by the target enzyme.SM analogues will be synthesised and incorporated into the membrane bilayer of drug-loaded liposomes. The ceramide analogue products they form on enzymatic reaction with SMase create drug-eluting pores in regions of high SMase activity (i.e. atherosclerosis) and release an encapsulated drug, but unlike natural ceramides do not interact with cells to trigger responses such as apoptosis. For the first time, toxicity of SM analogues and efficacy of the optimised liposome delivery vectors will be measured on human vascular endothelial cells using state-of-the-art live cell Raman microspectroscopy, which can highlight subtle differences in lipid and cholesterol production and distribution and cell cycle.This never before reported drug delivery platform can be translated to treat many SMase dysregulating pathologies and is a major breakthrough in liposomes for TRIGGERED drug delivery. The impact on health and society of locally treating these pathologies with SMase-targeting drugs cannot be overestimated.