A plasmon resonance system, instrument, cartridge, and methods for analysis of analytes is disclosed. A PR system is provided that may include a DMF-LSPR cartridge that may support both digital microfluidic (DMF) capability and localized surface plasmon resonance (LSPR) capability for analysis of analytes. In some examples, the DMF portion of the DMF-LSPR cartridge may include an electrode arrangement for performing droplet operations, whereas the LSPR portion of the DMF-LSPR cartridge may include an LSPR sensor. In other examples, the LSPR portion of the DMF-LSPR cartridge may include an in-line reference channel, wherein the in-line reference channel may be a fluid channel including at least one functionalized LSPR sensor (or sample spot) and at least one non-functionalized LSPR sensor (or reference spot). Additionally, methods of using the PR system for analysis of analytes are provided.