Bioorthogonal Activation of RCA-Based Amplifiable DNAzymes in Bimetallic NMOF for Precise Gene/Chemo-Dynamic Combination Therapy

Controllable and sufficient concentrations of therapeutic agents in gene therapy are critical to achieve satisfactory outcomes. Herein, a Zn²⁺/Cu²⁺ bimetallic nano metal–organic framework loaded with rolling circle amplification (RCA) substrates (termed PZCT) was established for precise and efficient DNAzyme-based gene and chemo-dynamic combined therapy. The activation of PZCT is bioorthogonally controlled by tumor-specific miR-21, which generates numerous DNAzyme for silencing EGR-1 mRNA with the assistance of Zn²⁺ from PZCT. Simultaneously, the doped copper ions on PZCT exert chemo-dynamic therapy (CDT) by reducing glutathione (GSH) and converting endogenous hydrogen peroxide (H₂O₂) into hydroxyl radical (·OH). These combination therapies exhibited remarkable tumor elimination effects in vivo and promised excellent tumor specificity via a bioorthogonal strategy. The proposed nanoplatform offers new prospects for precise cancer therapeutics by overcoming low transfection efficiency and off-target toxicity in DNAzyme-based approaches.