Combined photothermal therapy and nitric oxide (NO)-mediated gas therapy has shown great potential as a cancer treatment. However, the on-demand release of NO at a high concentration presents a challenge owing to the lack of an ideal bio-transducer with a high loading capacity of NO donors and sufficient energy to induce NO release. Here, we present a new 2D BiTiS 3 nanosheet that is synthesized, loaded with the NO donor (BNN6), and conjugated with PEG-iRGD to produce a multifunctional bio-transducer (BNN6-BiTiS 3 -iRGD) for the on-demand production of NO. The BiTiS 3 nanosheets not only have a high loading capacity of NO donors (750%), but also exhibit a high photothermal conversion efficiency (59.5%) after irradiation by a 1064-nm laser at 0.5 W/cm 2 . As a result of the above advantages, the temporal-controllable generation of NO within a large dynamic range (from 0 to 344 μM) is achieved by adjusting power densities, which is among the highest efficiency values reported for NO generators so far. Moreover, the targeted accumulation of BNN6-BiTiS 3 -iRGD at tumor sites leads to spatial-controllable NO release. In vitro and in vivo assessments demonstrate synergistic NO gas therapy with mild photothermal therapy based on BNN6-BiTiS 3 -iRGD. Our work provides insights into the design and application of other 2D nanomaterial-based therapeutic platforms.