A new class of nanoscale devices called ion-sensitive metal-semiconductor field-effect transistors (nano-IS-MESFET) for sensing applications is reported. Nanoparticle-nanowire hybrids with active metal-semiconductor regions are operated as ion-sensitive field-effect transistors (ISFETs) in liquids, where 0D metal gates induce quasi-spherical charge depletion regions in 1D transport channel producing stronger field-effects. As a proof-of-concept, we present ZnO nanowire-Pd/Au nanoparticle IS-MESFETs that show increased transconductance in comparison to ZnO nanowire ISFETs. As demonstrated further, ISMESFETs may also provide strategies for site-specific immobilization of receptor molecules paving way towards a novel electrical biosensing platform operable at low voltages with improved selectivity and sensitivity. (C) 2013 American Institute of Physics. [http://dx.doi.org/10.1063/1.4775579]