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The novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) continues to pose a substantial global health threat. Along with vaccines and targeted therapeutics, there is a critical need for rapid diagnostic solutions. In this work, we use computational protein modeling tools to suggest molecular beacon architectures that function as conformational switches for high-sensitivity detection of the SARS-CoV-2 spike protein receptor binding domain (S-RBD). Integrating these beacons on a miniaturized total internal reflection fluorescence (mini-TIRF) microscope, we detect the S-RBD and pseudotyped SARS-CoV-2 with limits of detection in the femtomolar range. We envision that our designed mini-TIRF platform will serve as a robust platform for point-of-care diagnostics for SARS-CoV-2 and future emergent viral threats.