In situ-activated photothermal nanoplatform for on-demand NO gas delivery and enhanced colorectal cancer treatment

The naturally evolved and intestinal pathogenic Fusobacterium nucleatum (Fn)-induced drug resistance profoundly impaired the efficacy of chemotherapy against colorectal cancer (CRC). Alternative treatment modalities against Fn-associated CRC are desperately needed. Herein, we engineer an in situ-activated anti-tumor and antibacterial nanoplatform (Cu2O/BNN6@MSN-Dex) to allow photoacoustic (PA) imaging-guided photothermal and NO gas combinatorial therapy for enhanced Fn-associated CRC treatment. The nanoplatform is constructed by loading cuprous oxide (Cu2O) and nitric oxide (NO) donor (BNN6) into dextran-decorated mesoporous silica nanoparticles (MSN), which is finally surface-functionalized with dextran via dynamic boronate linkage. Cu2O can be sulfuretted in situ by endogenous hydrogen sulfide overexpressed in CRC to produce copper sulfide with remarkable PA and photothermal properties, enabling the generation of NO from BNN6 under 808 nm laser irradiation, which is eventually triggered to release by multiple biological cues in the tumor microenvironment. Cu2O/BNN6@MSN-Dex exhibits superior biocompatibility, as well as H2S-triggered near-infrared-controlled antibacterial and anti-tumor performance in vitro and in vivo via photothermal and NO gas combination therapy. Furthermore, Cu2O/BNN6@MSN-Dex provokes systemic immune responses, thereby promoting anti-tumor efficacy. This study provides a conbinational strategy to effectively inhibit tumors and intratumor pathogens for enhanced CRC treatment. An in situ-activated nanoplatform was demonstrated to achieve significant CRC inhibition via synchronous intratumor Fn elimination and anti-tumor immune activation under PA imaging-guided PTT/NO gas combinatorial therapy. [Display omitted] •An in situ-activated anti-tumor and antibacterial nanoplatform is developed for enhanced Fn-associated CRC treatment.•The nanoplatform allows in situ generation of copper sulfide with PA and photothermal properties in H2S-overexpressed CRC.•NO can be asymptotically produced under NIR irradiation and released via the trigger of clues in CRC microenvironment.•The nanoplatform inhibits CRC under PA imaging-guided PTT/NO gas therapy by eliminating Fn and provoking immune responses.