Transformable binary-prodrug nanoparticles harness heterogeneity of neutrophils to overcome multidrug resistance and promote pyroptosis in cancer

•Morphological transformation of disulfide-bond-controlled transformable binary-prodrug nanoparticles (DSST@PSA).•Neutrophil-Mediated drug delivery system enhances antitumor therapeutic efficacy DSST@PSA downregulate P-Glycoprotein to overcome multidrug resistance.•DSST@PSA promote GSDMD cleavage-induced pyroptosis in tumor cells. Neutrophils, the most abundant myeloid cells, exhibit diverse phenotypic and functional variants in both homeostatic and disease conditions. The inherent heterogeneity of neutrophils positions them as promising candidates for drug carriers, facilitating precise drug delivery to tumor tissues and enhancing treatment accuracy and effectiveness. However, challenges arise from drug toxicity hindering neutrophil migration and the imperative need for efficient drug release at tumor sites. In response to these challenges, we have developed transformable binary-prodrug nanoparticles known as DSST@PSA. These nanoparticles manifest in two distinct forms: U-shaped and I-shaped. The U-shaped DSST@PSA variant demonstrates reduced toxicity and can be effectively transported to tumor sites through a neutrophil-mediated drug delivery system. Within the tumor microenvironment, the elevated glutathione concentration triggers a transformation of DSST@PSA into I-shaped structures. The I-shaped DSST@PSA variant exhibits the capability to overcome doxorubicin-induced multidrug resistance and promote pyroptosis in tumor cells. Our innovative DSST@PSA treatment strategy has demonstrated remarkable therapeutic effects in both in situ breast and metastatic mouse models. This breakthrough in neutrophil-mediated drug delivery systems significantly enhances treatment precision and efficacy. [Display omitted]