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.