Multicomponent reactions (MCRs) provide a facile one-pot approach to molecules with multiple chiral centers, which reveals a significant potential for the preparation of the libraries of chiral compounds. Utilization of nanoparticles (NPs) to catalyze MCRs further advances their synthetic value and versatility. NPs can be readily separated from reaction mixtures by filtration, centrifugation, or magnet-assisted separation of magnetic nanoparticles. Functionalization of nanoparticles is now widely explored as a powerful tool for the design and fine-tuning of catalytic properties of nanoparticles. This review focuses on the last decade’s progress in the utilization of the reversely polarized C-N bonds of cyanides and isocyanides as the versatile building units of a variety of heterocyclic and pharmaceutically relevant linear organic compounds.