A cascade-amplified Fe₃O₄-based nanoplatform for miRNA-21 sensing and combined apoptosis/ferroptosis induction

A miRNA-21-responsive analytical nanoplatform based on Fe₃O₄@polydopamine (PDA) was constructed for co-delivery of doxorubicin (DOX) and functional nucleic acids, with glucose oxidase (GOx) immobilized to achieve cascade-amplified combined therapeutic effects; notably, the proposed self-supplying oxidative cascade is a proof-of-concept deduction based on indirect evidence. The platform enables targeted recognition and specific binding to tumor cells via the sgc8 aptamer. Following cellular internalization, endogenous miRNA-21 triggers the catalytic hairpin assembly (CHA) reaction, enabling DOX release and DNAzyme generation with high specificity for miRNA-21 detection. The DNAzyme downregulates the expression of proliferation-promoting and ferroptosis-suppressing proteins, working in conjunction with DOX to promote tumor cell apoptosis. Concurrently, ferrous ions (Fe²⁺) released from Fe₃O₄ under GSH reduction react with H₂O₂ generated by GOx via the Fenton reaction, driving lipid peroxide accumulation and promoting ferroptosis. Experimental results indicate that the platform markedly reduces the viability of MCF-7 cells, exerting potent cytotoxicity. This study establishes a targeted multifunctional nanotherapeutic platform by integrating ferroptosis induction, gene modulation, and chemotherapeutic intervention with highly sensitive and selective miRNA-21 sensing capability. Aptamer substitution may enable adaptation to other tumor types in future in vivo studies, laying the groundwork for precision tumor therapy. Notably, this work is confined to in vitro cellular characterization, and comprehensive in vivo validation is required for translational assessment.