Sequential H 2 S‐Triggered Redox Relay Nanoprobes for Self‐Sustained Chem‐Illuminating Cascade Photodynamic Therapy

ABSTRACT Endogenous chemiluminescence offers a transformative approach to photodynamic therapy that circumvents the limited penetration of external light and enables tumor‐selective activation. However, most chemiluminescence‐driven photodynamic therapy (CL‐PDT) systems typically rely on intracellular oxidants (e.g., H 2 O 2 ) as chemiexcitation “fuels”, which conceptually contradicts the primary goal of elevating intratumoral oxidative stress. In this study, we report a sequential H 2 S‐triggered redox relay nano‐photosensitizer, NP‐Rubine, which addresses the fundamental “redox paradox” by decoupling photon generation from oxidation consumption. Composed of an H 2 S‐responsive chemiluminescent probe (Rubine) and a N ‐oxide scaffold (OPDEA‐Ppa), NP‐Rubine is selectively activated by endogenous H 2 S to initiate an efficiency chemiluminescence resonance energy transfer (CRET) cascade for efficient singlet oxygen ( 1 O 2 ) production. Concurrently, the N ‐oxide moiety promotes deep tumor penetration via transcytosis and depletes the intracellular NADPH pool. By synergistically coupling oxidant generation with reductant exhaustion, NP‐Rubine synergistically amplifies intracellular redox imbalance to induce apoptosis. In vivo studies substantiate that NP‐Rubine achieves exceptional deep‐tissue imaging and potent antitumor efficacy in HCT116 xenografts. This bio‐reductant, self‐sustained targeted CL‐PDT strategy circumvents the practical hurdles of oxidation‐fueled systems, offering a robust benchmark for precision nanomedicine in complex redox landscapes.