Pseudo natural products (NPs) feature structural novelty and diversity and thus are a new source of lead compounds for drug discovery. We first report the mesoporous silica nanoparticles (MSNs)-catalyzed de novo combination of benzodiazepine and isoindolinone, giving tetracyclic benzodiazepine-fused isoindolinone pseudo natural products (21 examples, 55–91% yields). The work also demonstrates that MSNs are efficient acidic catalysts for multi-component reactions.