Twin-Tail Tadpole-Shaped Ce6-Peptide Conjugate forEnhanced Photodynamic Cancer Therapy

Despite its therapeutic potential, photodynamic therapy faces several key limitations in clinical applications, including poor drug delivery and insufficient tumor selectivity. We engineered <b>RFYFYR-Ce6-RFYFYR (R-Ce6-R)</b>, a twin-tail peptide–photosensitizer conjugate that self-assembles into nanostructures for improved cancer treatment. By incorporating arginine-rich peptide sequences, this design not only enhances cellular internalization but also promotes peroxynitrite (ONOO^–) formation, amplifying the therapeutic effect. Our studies revealed that <b>R-Ce6-R</b> achieves 33-fold higher potency than unmodified Ce6, with an IC₅₀ of 0.18 μM. The conjugate demonstrated selective accumulation in tumor tissue, robust ROS generation, and complete tumor regression in animal models while maintaining a favorable safety profile. These results establish <b>R-Ce6-R</b> as an innovative approach for advancing photodynamic therapy in cancer treatment.