Fig. 1

a Synthetic route of cisplatin/l-arginine coupling prodrug; b Preparation of the “ion/gas” bioactive nanogenerator (IGBN); c Schematic illustration of IGBN reprograms the metastasis-promoting tumor microenvironment for metastasis-inhibited TNBC therapy. After internalized by tumor cells, IGBN could specifically produce Cu²⁺ in acidic lysosome, which catalytic oxidizing E2 to reduce E2 levels in tumor in situ. Meanwhile, the released Pt-Arg prodrug reduced into cisplatin to significantly promote the generation of H₂O₂ in the tumor, thus permitting self-augmented cascade NO gas generation by oxidizing Arg. Such a metastasis-promoting tumor microenvironment reprogramming (Cu²⁺ mediated E2 down-regulation and NO mediated platelet activation blockade) affords effective lung metastasis suppression. Notably, ion therapy, NO gas therapy and cisplatin chemotherapy together result in an enhanced therapeutic efficacy in primary TNBC ablation