Cascade Nanoreactors for In-Situ Peroxynitrite Generation via Pyrrole-Bridged NIR-II Type-I Photosensitizers to Enhance Tumor Phototherapy

Phototherapy holds great promise for cancer treatment due to its noninvasive nature, precise spatiotemporal control, and theranostic potential. However, its efficacy is often limited by the hypoxic and stroma-rich tumor microenvironment (TME), which restricts reactive oxygen species generation and drug penetration. Here, we present a multifunctional cascade nanoreactor that integrates NIR-II type-I photodynamic therapy, photothermal therapy, and gas therapy for enhanced tumor ablation. The platform is based on an aggregation-induced emission luminogen (AIEgen), TBT-PyT, capable of efficient O₂^-· generation and strong photothermal conversion under 808 nm laser irradiation. A heat-sensitive nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine, is coloaded to enable controlled NO release. The resulting in situ generation of peroxynitrite (ONOO^-) from O₂^-· and NO leads to amplified oxidative stress, extracellular matrix degradation, and improved therapeutic penetration. This work demonstrates a rational design strategy to overcome TME-associated barriers and advance precision cancer phototherapy.