Synergistic Comprehensive Activation Methods for Dual‐Modality PDT and Hypoxia‐Triggered Chemotherapy Guided by NIR‐II Imaging beyond 1700 nm in Deep Tumors

Abstract Although photodynamic therapy (PDT) holds great promise for applications in cancer treatment, it has limited effectiveness against deep hypoxic tumors. Moreover, the lack of visualization guidance for precision theranostics poses additional challenges, hindering its broader clinical adoption. By combining NIR‐IIc (1800 nm) imaging guidance with internally and externally activatable dual‐modality PDT and hypoxia‐triggered chemotherapy, this study proposes a conceptual framework to overcome these limitations. This approach involves the use of photoswitchable lanthanide‐doped nanoparticles featuring Tm 3+ ‐activated upconversion/downshifting emissions coupled with carboxyl‐terminated Ir(III) complex‐based Type I/II photosensitizer to form a nanophotosensitizer. The findings demonstrate that this system enabled NIR‐IIc imaging guidance upon 808/980 nm excitation while selectively activating external PDT under 980 nm irradiation, thereby ensuring accurate therapy and minimizing phototoxicity risk. The Ir(III) complex conjugates with luminol to form a self‐illuminating Type I/II photosensitizer, which can respond to the elevated H 2 O 2 levels in the tumor microenvironment, effectively catalyzing chemiluminescence‐assisted PDT. Moreover, PDT aggravates tumor hypoxia, which in turn activates the hypoxia‐activatable prodrugs like tirapazamine, resulting in a synergistic antitumor effect. With NIR‐IIc imaging‐guided dual‐modality PDT, this study introduces a groundbreaking approach that unites Type I/II PDT with chemotherapy, significantly advancing the precise and effective treatment of deep hypoxic tumors.