Due to the high prevalence of risk factors such as smoking and human papillomavirus infection, head and neck cancers are a particular threat to individuals in low-income, underserved communities. Because of limited access to screening tools for early cancer detection to reduce mortality and morbidity, they have diminishing chances of long-term survival. Cancer mortality and morbidity in these areas will not see a reduction without the development of practical and easily accessible diagnostic methods and instrumentation. To address these limitations, we propose to develop and validate a nanophotonics-enhanced molecular assay based on ultrabright surface-enhanced Raman scattering (SERS) “nanorattle” probes for multiplexed detection of biomarkers of squamous cell carcinoma; this cancer accounts for about 85% of all head and neck cancers. For analytical validation, our assay method will be tested on clinical samples, such as fresh tissue and brush cytology biopsies. Brush cytology is a form of non-invasive biopsy performed without the need of surgical or specialized care. By combining “lab-on-a-stick” technology with ultrabright SERS nanorattles, the assay concept provides a unique rapid ‘sample-to-answer’ approach. Our molecular analysis technology is designed to be integrated in a portable device, referred to as Raman Assay using Plasmonics for Identification and Diagnosis (RAPID). We envision the RAPID technology to be deployed as a low-cost diagnostic tool capable of point-of- care head and neck cancer identification, with the potential to reduce the morbidity and mortality of this disease in underserved populations due to early detection of cancer. The project’s aims are the following: (1) Develop nanoplasmonic-based nanorattle probes for multiplex detection of head and neck cancer molecular biomarkers; (2) Integrate the molecular analysis method into a simple-to-use, automated and portable point-of-care device; (3) Evaluate and validate the molecular analysis method for diagnosis in tissue samples and brush cytology biopsies; and (4) Deploy the technology for implementation at the point-of-care in an underserved community setting. The implications of the RAPID method are vast and significant for cancer research as well as diagnostics, especially in the setting of underserved populations. For patients presenting with a suspicious head and neck lesion, our method can provide a rapid diagnosis, allowing for earlier treatment before the onset of distant metastases. This novel technology will also allow direct mRNA biomarker detection for research on cancer development and progression. Compared to laboratory-based histopathologic diagnosis, requiring specialized equipment and trained operators for qRT-PCR and often taking weeks or even months in remote regions, the RAPID method can be completed in less than an hour at the point of need. Ultimately, the integration of this molecular method into a portable device will allow for clinical translation...