NIR-triggered programmable nanomotor with H2S and NO generation for cascading oncotherapy by three-pronged reinforcing ICD

Gas therapy (GT) and/or phototherapy have been recently employed as immunogenic cell death (ICD) agents for activating immunotherapy, whereas the effective activation of sufficient immune responses remains an enormous challenge in such single therapeutic modality. In this study, a near-infrared (NIR)-triggered programmable nanomotor with hydrogen sulfide (H₂S) and nitric oxide (NO) generation is well designed to achieve oncotherapy by cascading mild photothermal, gas, and reactive oxygen species (ROS)-reinforced immunogenic cell death. In brief, a gas signal molecule donor NOSH with H₂S and NO capable of on-demand H₂S and NO release was synthesized and then loaded into hollow mesoporous copper sulfide nanoparticles (termed as HCuSNPs) with an inherent NIR absorption and surface modification activity to obtain the programmable nanomotor (termed as NOSH@PEG-HCuSNPs). In particular, NOSH@PEG-HCuSNPs can effectively achieve the simultaneous spatiotemporal co-delivery of NOSH and HCuSNPs, thereby exerting the synergistic effects of GT and mild photothermal therapy (mPTT). It is worth noting that the anti-tumor response of mPTT is effectively enhanced by GT by disrupting the mitochondrial respiratory chain, inhibiting ATP production, and promoting tumor cell apoptosis. One by one, a large number of peroxynitrite anion (ONOO^-) radicals are generated by the interactions of ROS from mPTT and NO from NOSH. Meanwhile, the unique protective mechanism of H₂S is utilized to induce tumor thermal ablation by reducing the overexpression of heat shock protein 90 (HSP 90) and minimize the unnecessary damage toward normal tissues. Finally, ICD is markedly augmented by the cascading effects of mPTT, ONOO⁻radicals, and H₂S. Concurrently, the immunosuppressive tumor microenvironment is reprogrammed, effectively inhibiting distant tumor tissues and preventing metastasis and tumor recurrence. Taken together, this study provides a new perspective for innovation in the field of oncotherapy.