The precise delivery and controllable release of carbon monoxide (CO) to tumor tissues is an emerging anticancer therapy because CO in a high dose can be detrimental to cell survival and tumor growth. However, CO gas therapy is limited by the gaseous nature of CO that hinders its enrichment and controllable release to tumor tissues. Here, a novel photodynamic therapy (PDT)-driven CO controllable release system (CORM@G3DSP-Ce6) that integrates the photosensitizer chlorin e6 (Ce6) and H 2 O 2 -sensitive CO releasing molecule CORM-401 into peptide dendrimer-based nanogels (G3DSP) is described. Upon excitation with near-infrared light, Ce6-mediated photochemical effect not only promotes the efficient cellular internalization of CORM@G3DSP-Ce6, but also triggers the rapid intracellular CO release from CORM-401 by depleting the H 2 O 2 produced during PDT. Importantly, the PDT-driven CO release does not impair the generation capability of singlet oxygen ( 1 O 2 ). As a result, accompanied with the simultaneous generation of large amounts of 1 O 2 and CO in cells, the combination of PDT and CO gas therapy offers significant synergistic anticancer effects and superior therapeutic safety both in vitro and in vivo.CORM-401 is a novel water-soluble CORM with multifaceted therapeutic potential. [11] First, the amount of CO released from CORM-401 is much higher than other CORMs. It is three times higher than commercially available CORM-3. CORM-401 is relatively stable. It is stable in phosphate buffered saline (PBS, pH 7.4) for several hours and thus will not likely release CO prematurely during circulation. CORM-401 releases CO via oxidation. The release rate is significantly increased in the presence of biologically relevant oxidants, such as hydrogen peroxide (H 2 O 2 ), [11,12] suggesting that CORM-401 is capable of intracellular release of CO, as long as CORM-401 can be efficiently delivered to the cells with significantly elevated H 2 O 2 levels.Photodynamic therapy (PDT) is a clinically approved and minimally invasive cancer treatment. The therapeutic effect of PDT is attributed to the large amounts of reactive oxygen species (ROS) produced by photosensitizer (PS) under NIR light. This induces rapid apoptosis of cancer cells. [13] The ROS generated by PS under a short period of low energy density irradiation can increase the cell membrane permeability and enhance the cellular uptake of nanoparticles-this is known "photochemical internalization" (PCI). [14] In addition, the PDT process is always accompanied by intracellular production of H 2 O 2 -one of the most stable agent of ROS. These unique merits make PDT an ideal candidate to promote the cellular uptake of CORM-401 and drive intracellular CO release. Moreover, PDT itself is also an anticancer treatment strategy. When used in tandem, these tools could significantly improve the anticancer effects.However, it remains unclear whether taking advantage of PDT effect for driving intracellular CO release would weaken the anticancer effects of PDT. Singlet oxygen ( 1 O 2...