Fast, efficient, and accurate detection of SARS-CoV-2 spike antigen is pivotal to control the spread and reduce the mortality of COVID-19. Nevertheless, the sensitivity of available nanobiosensors to detect recombinant SARS-CoV-2 spike antigen seems insufficient. As a proof-of-concept, MOF-5/CoNi₂S₄ is developed as a low-cost, safe, and bioactive hybrid nanostructure via the one-pot high-gravity protocol. Then, the porphyrin, H₂TMP, was attached to the surface of the synthesized nanomaterial to increase the porosity for efficient detection of recombinant SARS-CoV-2 spike antigen. AFM results approved roughness in different ranges, including 0.54 to 0.74 μm and 0.78 to ≈0.80 μm, showing good physical interactions with the recombinant SARS-CoV-2 spike antigen. MTT assay was performed and compared to the conventional synthesis methods, including hydrothermal, solvothermal, and microwave-assisted methods. The synthesized nanodevices demonstrated above 88% relative cell viability after 24 h and even 48 h of treatment. Besides, the ability of the synthesized nanomaterials to detect the recombinant SARS-CoV-2 spike antigen was investigated, with a detection limit of 5 nM. The in-situ synthesized nanoplatforms exhibited low cytotoxicity, high biocompatibility, and appropriate tunability. The fabricated nanosystems seem promising for future surveys as potential platforms to be integrated into biosensors.