Self-Assembly of Intelligent Nanoplatform for Endogenous H₂S‑Triggered Multimodal Cascade Therapy of Colon Cancer

The specific in situ generation and activation of therapeutic agents with high spatiotemporal precision is expected to revolutionize cancer treatment. Here, we develop an intelligent nanoplatform (termed as NP-Cu), which is constructed by assembling photosensitizer chlorin e6 (Ce6), hypoxia-responsive prodrug banoxantrone (AQ4N) with clickable dibenzocyclooctyne (DIBO) functionalized lysine (D-K), and cyclen-Cu²⁺ complex, for improving combination anticancer therapy. Cyclen-Cu²⁺ complex-induced photodynamic therapy (PDT) quenching in NP-Cu can be effectively and selectively activated by tumor-overproduced hydrogen sulfide (H₂S). More importantly, the reaction of endogenous H₂S with Cu²⁺ can generate photothermal agent copper sulfide (CuS) for photothermal therapy (PTT). Furthermore, with the activation of PTT and PDT, intracellular hypoxic stress is amplified to trigger AQ4N-associated chemodynamic therapy (CDT), leading to light-enhanced cascade therapy of PDT, PTT and CDT. Therefore, we present a simple and practical strategy for developing pathological stimuli responsive combination therapy, which has the potential of advancing precision cancer medicine.