A Sequentially Activated Nanoreactor With DNAzyme Cascade for Precise Breast Cancer Theranostics

Current oncological interventions are often limited by insufficient tumor selectivity and off‐target toxicities, necessitating intelligent therapeutic platforms with precision‐gated activation. In this study, a sequentially activated nanoreactor (GOx‐MnCaP‐DD) is designed for integrated breast cancer theranostics, combining precision chemotherapy with starvation‐enhanced chemodynamic therapy (CDT). The platform is constructed by biomineralizing glucose oxidase (GOx)‐templated manganese‐doped calcium phosphate (MnCaP), followed by surface functionalization with DOX‐encapsulated DNA hairpins (H1 and H2). In the acidic tumor microenvironment, the MnCaP scaffold first degrades, releasing the payloads and exposing the DNA hairpins. Subsequently, overexpressed miRNA‐21 triggers H1 hybridization, initiating DOX release and exposing a functional DNAzyme sequence. With Mn 2+ as a cofactor, the DNAzyme continuously cleaves H2, enabling cascade‐amplified DOX release for sensitive miRNA detection (limit of detection: 210 fM) and enhanced chemotherapy. Simultaneously, GOx‐mediated glucose depletion induces starvation while generating gluconic acid and H 2 O 2 , which accelerates nanoreactor disintegration and fuels Mn 2+ ‐mediated CDT through a self‐reinforcing loop. Both in vitro and in vivo studies demonstrate improved therapeutic specificity and antitumor efficacy, providing a sophisticated strategy for “smart” nanomedicines capable of autonomous signal amplification and synergistic treatment.