Trilocked Photodynamic Senolytic Inducer Potentiating Immunogenic Senescent Cell Removal for Liver Fibrosis Resolution

Liver fibrosis is a major global health problem without effective therapies, and targeted elimination of senescent cells is beneficial for hepatic function and organism survival. We report a new trilocked photodynamic senolytic inducer (PDSI) strategy for liver fibrosis resolution using a type-I photodynamic agent for immunogenic clearance of senescent cells. We demonstrate that this trilocked PDSI not only facilitates efficient production of superoxide anions (O2•–) in lysosomes of senescent cells for photodynamic therapy, but also permits NIR fluorescence and photoacoustic (NIRF/PA) imaging of senescent cells. Mechanistic investigation reveals that the trilocked PDSI elicited senescent cell clearance predominantly via the immunogenic necroptosis pathway. Moreover, this PDSI with a liver-targeting moiety enables high-contrast NIRF/PA imaging and effective liver fibrosis resolution in vivo. This liver-targeting PDSI exhibits remarkable immunogenic ablation of senescent cells, with enhancing dendritic cell maturation and cytotoxic T cell recruitment in liver fibrosis. Our study highlights the potential of trilocked type I PDSI for boosting immunity for senescent cell clearance and liver fibrosis treatment.