Dual-Responsive Peptide-Photosensitizer Conjugate Based on a Hypocrellin Derivative for Tumor-Targeted Photodynamic Therapy

• • Dual-lock activation: B-HCPP-RGD releases the type I PS HCEA only when both H2O2 and cathepsin B are present; ROS generation in solution is effectively suppressed in the absence of either stimulus. This prevents premature activation in circulation and reduces off-target phototoxicity, a persistent clinical liability of always-on PSs. • • Targeting specificity: covalent conjugation of cRGD confers specific recognition of αVβ3 integrin receptors overexpressed on tumor neovasculature and cancer cell membranes. In vitro, the conjugate exhibits almost no phototoxicity toward normal cells while producing significant phototoxicity toward tumor cells, widening the therapeutic window. • • Hypoxia tolerance: B-HCPP-RGD retains strong phototoxicity toward tumor cells even under hypoxic conditions, attributable to the type I ROS mechanism of the released HCEA. This addresses the oxygen-dependence bottleneck that limits conventional type II PSs in solid tumors. • • In vivo efficacy and safety: the conjugate actively targets tumor tissue and achieves a high tumor inhibition rate in vivo with high biosafety, supporting further preclinical development of dual-responsive peptide-PS conjugates for precision PDT.