High‐Contrast Photoacoustic Imaging of Localized Cysteine in Orthotopic Breast Cancer Enabled by A Totally‐Caged Methylene Blue Probe

High-contrast photoacoustic sensing imaging (PASI) was greatly determined by optical absorption changes of the absorbers usually enabled by activatable probes via controllably converting the absorbed electromagnetic energy to ultrasound waves. However, most of current photoacoustic probes still suffer from limited imaging contrast towards specific species because of their small absorption spectral changes in the near infrared (NIR) region. Herein, we developed a methylene blue-based photoacoustic probe with its NIR optical absorption totally caged, which could afford dramatical "OFF-to-ON" absorption transition for high-contrast photoacoustic imaging towards the localized cysteine. The rationally designed methylene blue-based probe for cysteine (MB-Cys) would keep in off state with almost no absorption in NIR region, while upon activated by cysteine through cyclization reaction with acrylates, it would reconstruct the π-conjugation system to release the free methylene blue with strong absorption centered at 665 nm (>130-fold enhancement). The unique responsive behavior could enable the PASI for photoacoustic mapping the cysteine in orthotopic breast cancer in a high-contrast manner. Therefore, this work established an up-to-date strategy to originally eliminate the background photoacoustic signal for PASI to accurately monitor cysteine in vivo.