Simple SummaryLate diagnosis and chemoresistance are key obstacles to ovarian cancer treatment success. Thus, there exists a need to develop new markers to detect ovarian cancer at an early stage as well as predict chemoresistance. We have developed a nanosensor platform that reacts with extracellular vesicles and cisplatin as well as predicts early-stage cancers and chemoresistance. Mechanistically, we have shown that chemoresistant OVCA cells produce large amounts of plasma gelsolin (pGSN) that induces increased production of small extracellular vesicles as a means of exporting cisplatin from the cell. This helps to prevent cisplatin-induced apoptosis in chemoresistant cells.AbstractBackground: Ovarian cancer (OVCA) is the most fatal gynecological cancer with late diagnosis and plasma gelsolin (pGSN)-mediated chemoresistance representing the main obstacles to treatment success. Since there is no reliable approach to diagnosing patients at an early stage as well as predicting chemoresponsiveness, there is an urgent need to develop a diagnostic platform for such purposes. Small extracellular vesicles (sEVs) are attractive biomarkers given their potential accuracy for targeting tumor sites. Methods: We have developed a novel biosensor which utilizes cysteine-functionalized gold nanoparticles that simultaneously bind to cisplatin (CDDP) and plasma/cell-derived EVs, affording us the advantage of predicting OVCA chemoresponsiveness, and early diagnosis using surface-enhanced Raman spectroscopy. Results: We found that pGSN regulates cortactin (CTTN) content resulting in the formation of nuclear- and cytoplasmic-dense granules facilitating the secretion of sEVs carrying CDDP; a strategy used by resistant cells to survive CDDP action. The clinical utility of the biosensor was tested and subsequently revealed that the sEV/CA125 ratio outperformed CA125 and sEV individually in predicting early stage, chemoresistance, residual disease, tumor recurrence, and patient survival. Conclusion: These findings highlight pGSN as a potential therapeutic target and provide a potential diagnostic platform to detect OVCA earlier and predict chemoresistance; an intervention that will positively impact patient-survival outcomes.