Self‐Assembly of H2S‐Generating Photosensitizer for Gas‐Assisted Synergistic Photothermal Therapy

Photothermal therapy (PTT) is emerging as a promising cancer treatment, but uneven heat distribution increases side effects and reduces treatment precision, where high-temperature zones risk inducing undesired inflammation, while low-temperature regions are insufficient due to upregulation of heat shock proteins (HSPs). Herein, a gas-assisted PTT strategy is designed to link near-infrared heptamethine cyanine (Cy7) with self-immolative phenyl thiocarbonate (PTC), a hydrogen sulfide (H2S) donor through a disulfide bond, creating a small-molecule photosensitizer (Cy7-SS-PTC) that can self-assemble into nanoparticles (NPs) without stabilizers. Upon internalized by cancer cells, Cy7-SS-PTC NPs respond to elevated glutathione levels, and simultaneously release Cy7 and H2S via a cascade reaction. The released Cy7 reassembles into nanoaggregates, generating hyperthermia under 808 nm light irradiation, and then binds to albumin, producing strong near-infrared fluorescence to track tumors for precise treatment. The released H2S not only disrupts the mitochondrial respiratory chain, blocks ATP production, and suppresses HSP70 overexpression to amplify the efficacy of low-temperature PTT regions but also curbs proinflammatory cytokines in high-temperature PTT zones, delivering powerful tumor ablation with minimal inflammation. This small-molecule-based "H2S-assisted PTT" strategy optimizes the current PTT and validates its potential clinical application.