Efficient Polysulfide‐Based Nanotheranostics for Triple‐Negative Breast Cancer: Ratiometric Photoacoustics Monitored Tumor Microenvironment‐Initiated H2S Therapy

Abstract The incidence of triple‐negative breast cancer (TNBC) is difficult to predict, and TNBC has a high mortality rate among women worldwide. In this study, a theranostics approach is developed for TNBC with ratiometric photoacoustic monitored thiol‐initiated hydrogen sulfide (H 2 S) therapy. The ratiometric photoacoustic (PA) probe (CY) with a thiol‐initiated H 2 S donor (PSD) to form a nanosystem (CY‐PSD nanoparticles) is integrated. In this theranostics approach, H 2 S generated from PSD is sensed by CY based on ratiometric PA signals, which simultaneously pinpoints the tumor region. Additionally, H 2 S is cytotoxic toward TNBC cells (MDA‐MB 231), showing a tumor inhibition rate of 63%. To further verify its pharmacological mechanism, proteomics analysis is performed on tumors treated with CY‐PSD nanoparticles. Cells are killed by the significant mitochondrial dysfunction via supressed energy supply and apoptosis initiation. Besides, the observed inhibition of oxidative stress also generates the cytotoxicity. Significant Kyoto Encyclopedia of Genes Genomes pathways related to TNBC are found to be inhibited. This H 2 S theranostics approach updates the current anticancer therapies which brings promise for women suffering malignant breast cancer.