Nipping disease in the bud: nSMase2 inhibitors as therapeutics in extracellular vesicle-mediated diseases

•Extracellular vesicles (EVs) are potent vehicles of intercellular communication.•EVs can transport pathological cargo that contributes to disease.•One pathway of EV biogenesis is dependent upon ceramides generated by nSMase2.•Inhibition of nSMase2 shows promise in treating diseases that propagate via EVs.•Potent and selective nSMase2 inhibitors have recently been discovered. Extracellular vesicles (EVs) are indispensable mediators of intercellular communication, but they can also assume a nefarious role by ferrying pathological cargo that contributes to neurological, oncological, inflammatory, and infectious diseases. The canonical pathway for generating EVs involves the endosomal sorting complexes required for transport (ESCRT) machinery, but an alternative pathway is induced by the enrichment of lipid membrane ceramides generated by neutral sphingomyelinase 2 (nSMase2). Inhibition of nSMase2 has become an attractive therapeutic strategy for inhibiting EV biogenesis, and a growing number of small-molecule nSMase2 inhibitors have shown promising therapeutic activity in preclinical disease models. This review outlines the function of EVs, their potential role in disease, the discovery and efficacy of nSMase2 inhibitors, and the path to translate these findings into therapeutics.