Schematic diagram of the mitochondria-targeted novel black phosphorus nanosheets platform for the cascaded gas/mild photothermal/photodynamic synergistic therapy of tumor. BP: black phosphorus, Ce6: chlorin e6, SNP: sodium nitroprusside dihydrate, NO: nitric oxide, mPTT: mild photothermal therapy, PDT: photodynamic therapy. Display omitted •BCS platform shows high specific capability to mitochondria of tumor.•The intelligent releasing to the tumor environment and NIR with the BCS.•The BCS blocks the function of mitochondrial and perturbs the lysosomes.•The BCS shows three-staged cascaded GT/mPTT/PDT synergistic therapeutic. The mitochondria critically determine the cell fates and therapeutic interventions. Contrary to the conventional and prevalent nanomaterial-based antitumor strategy, this study proposed a novel synergistic solution that accomplied with a dual tumor and mitochondria-specific BP@PDA-Ce6&SNP-TPP&FA (BCS) platform. The Ce6 and SNP were released in response to the tumor microenvironment and 660 nm laser irradiation. This induced the generation of NO, mild temperature, and ROS, and a second dynamic therapy (ONOO−), destroying the mitochondrial structure and inhibiting the mitochondrial function. The blockade of the mitochondrial function would hinder the cellular respiration and ATP supply, and also perturb the communication and cellular components between the mitochondria and lysosomes. Consequently, the BCS NPs exhibited better antitumor efficacy as well as excellent biosafety than the gas therapy (GT), mild photothermal therapy (mPTT), or photodynamic therapy (PDT) nanoagents individually. This novel cascaded GT/mPTT/PDT synergistic solution offering great potential for numerous anti-cancer treatments.