A Gas Phototheranostic Nanocomposite Integrates Photothermal Molecule With Thermal‐Sensitive Nitric Oxide Donor for Anticancer Therapy

ABSTRACT Photothermal therapy (PTT) has emerged as a promising strategy for tumor treatment, owing to its exceptional treatment outcomes and spatiotemporal control. However, persistent challenges, such as high‐energy laser‐induced damage to surrounding tissue and induces a cascade of heat shock responses (HSRs) in tumor cells, collectively contribute to suboptimal therapeutic outcomes. In addition, single‐modality treatment approaches often fail to attain optimal therapeutic efficacy. In this study, we designed a gas/PTT nanocomposite material (PTZSCN‐NO NPs) that integrates the photothermal molecule phenothiazin‐thiophen‐dimethylfuran (PTZSCN) with a thermosensitive nitric oxide (NO) donor (S‐nitroso‐N‐acetylpenicillamine, SNAP). Upon laser irradiation, PTZSCN generates heat for PTT and promotes the release of NO from SNAP, can inhibit the expression of multiple HSPs, thus enhancing the efficacy of PTT. Furthermore, upon light exposure, PTZSCN‐NO NPs generate a photothermal effect, leading to mitochondrial damage, caspase‐1 activation, and gasdermin D cleavage. These events ultimately induce pyroptosis, achieving a synergistic gas/photothermal therapeutic effect and suppressed orthotopic breast tumor growth and metastasis in a tumor‐bearing mice model. This approach optimizes conventional PTT and providing a repeatable, noninvasive treatment process.