The mild photothermal therapy of solid tumors was still bottlenecked by the uneven temperature distribution in tumor tissue and the autophagy-mediated resistance. Here, we leveraged the ultra-small size (approximately 0.32 nm) and autophagy inhibitory property of nitric oxide (NO) to overcome these limitations for enhanced gas-photothermal therapy of large tumors. An NO donor was loaded into mesoporous polydopamine and coated with tumor cell membranes for tumor-targeting delivery. The acid-triggered release of NO potently inhibited autophagy to block the pro-survival pathway of tumor cells. Besides, as a small-molecule gas, it diffused freely into deep regions and precisely eliminated the deep-seated tumor cells, resulting in approximately 90% tumor inhibition in the late-stage breast tumor model (>500 mm³). The NO gas therapy shows great potential for complementing other therapeutics for the synergistic therapy of large solid tumors.

Nitric oxide  /  Autophagy inhibition  /  Mild photothermal therapy  /  Deep penetration  /  Gas therapy  /  Apoptosis  /  Cell membrane  /  Solid tumor