In the search for surface modifications that minimizes the influence on the structure and function of adsorbed proteins, supported phospholipid bilayers (SPBs) have been proven inert towards protein adsorption from as complex mixtures as serum. Since they at the same time fulfils the requirements set on specific coupling of both water-soluble and membrane bound proteins, have made them attractive in various biosensor applications and as coatings for biomaterials. However, so far limited progress has been made with respect to SPB formation on nanoscale solid supports. By utilizing insights gained from quartz crystal microbalance with dissipation (QCM-D) monitoring of protein/lipid interactions on either Au or SiO2, we have established a surface-modification protocol that enables localized rupture of phospholipid vesicles on SiO2 in the bottom of nanometric holes in a thin Au film. The hole-induced localization of the localized surface plasmon resonance (LSPR) field to the voids of the holes is demonstrated to provide a novel concept for studies of protein-binding reactions confined exclusively to SPB-patches supported on SiO2.@footnote 1@ In particular, we emphasize the possibility to in this way perform label-free studies of lipid-membrane mediated reaction kinetics, including the compatibility of the assay with array-based recording, with signals originating from bound protein in the sub-zeptomole regime. Extensions of this concept includes the use of the conductive LSPR hole substrate (i) as one of the electrodes of the QCM-D sensors, enabling simultaneous QCM-D and LSPR readouts of reactions occurring on, for example, either Au or SiO2, and (ii) for studies of protein binding to individual colloidal particles that match the size of the holes. @FootnoteText@ @footnote 1@Svedhem S, Pfeiffer I, Larsson C, Wingren C, Borrebaeck C, Höök F. ChemBioChem 2003:339-343. @footnote 2@Dahlin A, Zach M, Rindzevicius T, Kall M, Sutherland DS, Hook F. JACS 2005, 127:5043-5048.