Precise Diffusion of Gaseous H 2 S “Bomb” Potentiates NIR‐II Imaging‐Guided Photothermal Therapy by Relieving Heat Tolerance and Disturbing Cellular Homeostasis for Synergistic Orthotopic Glioblastoma Treatment

Abstract Although photothermal therapy (PTT) has thrived as a novel cancer treatment method with the merits of high spatiotemporal specificity and minimal invasion, the limited penetration depth and poor blood−brain barrier permeability pose significant challenges in glioblastoma (GBM) treatment. Here, a near‐infrared‐II (NIR‐II) emissive nanosystem based on aggregation‐induced emission photothermal agents and H 2 S prodrug for brain‐targeted orthotopic GBM synergistic therapy is innovatively developed. It achieves through‐skull tumor visualization by NIR‐II/photothermal imaging, assisting in real‐time monitoring of GBM in the brain area. Moreover, the in situ released H 2 S triggered by photothermal stimulation efficiently infiltrates deep tumors and evokes mitochondrial dysfunction and cellular apoptosis. The gas therapy can also deplete ATP and subsequently downregulate HSP90 expression, thus inhibiting the heat tolerance of lethal tumors and enhancing PTT for GBM. Incorporating non invasive H 2 S gas “bomb” in GBM therapy may drive the clinical application of PTT, reducing the risk of incomplete tumor cell eradication due to intrinsic resistance to thermal.