Enabling Photoacoustic Imaging and Photothermal Elimination of Senescent Cells via an Activatable Theranostic Probe

Abstract Excessive accumulation of senescent cells disrupts tissue homeostasis, induces chronic inflammation and tumorigenesis, and ultimately accelerates senescence-associated dysfunction and malignant progression. Developing reliable tools for the detection and elimination of senescent cells is critical for the precise diagnosis and timely intervention of aging-associated diseases. However, existing senolytic theranostic probes suffer from oxygen-dependent photodynamic therapy (PDT) efficacy and the inherent limitations of fluorescence imaging in penetration depth and spatial resolution. Herein, we report the first theranostic probe RPM-Gal that integrates senescence-associated β-galactosidase-activated photoacoustic imaging and photothermal elimination of senescent cells. RPM-Gal is assembled by tethering a β-D-galactopyranoside moiety to a rhodol-derived polymethine scaffold (RPM-OH) via a self-immolative benzyl spacer. In vitro tests demonstrate that RPM-Gal possesses an excellent photoacoustic response and outstanding photothermal behavior against β-galactosidase. It is found that the overexpressed β-galactosidase in senescent cells can specifically activate the PA signal and the PTT effect of RPM-Gal upon light irradiation. This probe has been further successfully implemented for PA imaging and photothermal elimination of senescent tumor cells in vivo, establishing a targeted avenue for effective senolytic therapy.