Synergistic Effects of Activatable Photodynamic Therapy and Crisaborole for Psoriasis through Senolysis and Immunomodulation

Psoriasis is a multifactorial inflammatory disorder characterized by therapeutic resistance and high recurrence rates, with complex unmet clinical demands necessitating novel therapeutic strategies. Recently, emerging evidence has revealed pathological accumulation of senescent cells (SnCs) in psoriatic lesions, suggesting their critical involvement in disease persistence and relapse. Our previous studies demonstrated that precision photodynamic therapy (PDT) effectively eliminates SnCs and mitigates senescence-associated pathologies, positioning senotherapy as a potential breakthrough for psoriasis management. Building on these foundations, we developed SnC-targeted photosensitizers (H2O2-activated TZ0953 and β-gal-activated TZ0993) and revealed that SnC-targeted PDT significantly alleviates psoriatic pathology in psoriasis model mice. Further optimization led to a combination strategy employing TZ0953 with crisaborole, implementing dual-pathway intervention of the clearance of SnCs and inflammatory microenvironment modulation. This "dual-target" approach demonstrated superior efficacy compared to monotherapies. Our work pioneers a "dual-target/modal" strategy and addresses both cellular senescence and inflammatory cascades in psoriasis, providing a novel strategic direction for psoriasis treatment optimization.