Surface plasmon polariton excited in a back-side plasmon excitation geometry enable simultaneous soft ionization of both polar and nonpolar molecules through a unified hot-carrier mechanism. By tuning interfacial energy partitioning between hot-carrier-driven ionization and electron-phonon coupling mediated desorption, Surface plasmon polariton laser desorption ionization further achieves selective ionization of structural, positional, and stereochemical epimeric isomers, transforming laser desorption/ionization into a tunable interfacial reaction.