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.