Photo‐Triggered Cascade Therapy: A NIR‐II AIE Luminogen Collaborating with Nitric Oxide Facilitates Efficient Collagen Depletion for Boosting Pancreatic Cancer Phototheranostics

The dense extracellular matrix (ECM) in the pancreatic cancer severely hampers the penetration of nanodrugs, which causes inferior therapeutic efficacy. To address this issue, a multifunctional liposome, namely, Lip-DTI/NO, integrating a type-I photosensitizer DTITBT with glutathione (GSH) or heat-responsive nitric oxide (NO) donor S-nitroso-N-acetyl-D-penicillamine (SNAP) is constructed to deplete the tumor ECM, leading to enhanced drug delivery and consequently improved phototherapy. The loaded DTITBT possesses multiple functions including NIR-II fluorescence imaging, efficient superoxide radical (O₂ ^•-) generation and excellent photothermal conversion efficiency, making it feasible for precisely pinpointing the tumor in the phototherapy process. Responding to the intracellular overexpressed glutathione or heat produced by photothermal effect of DTITBT, NO can be released from SNAP. Upon 808 nm laser irradiation, Lip-DTI/NO could selectively induce in situ generation of peroxynitrite anion (ONOO^-) in tumor after cascade processes including O₂ ^•- production, GSH or heat-triggered NO release, and rapid reaction between O₂ ^•- and NO. The generated ONOO^- could activate the expression of endogenous matrix metalloproteinases which could efficiently digest collagen of tumor ECM, thus facilitating enhanced penetration and accumulation of Lip-DTI/NO in tumor. In vivo evaluation demonstrates the notable therapeutic efficacy via ONOO^--potentiated synergistic photodynamic-photothermal therapies on both subcutaneous and orthotopic pancreatic cancer model.