A Zeolitic Pyrimidine Framework (ZPF) Nanoplatform Co-Delivers a DNAzyme and a Protein Prodrug for Cascade-Activated...

The therapeutic application of cytotoxic proteins like ribonuclease A (RNase A) is hindered by their systemic toxicity. Here, we engineer a protein-structure-directed zeolitic pyrimidine framework (ZPF) as a superior nanocarrier that co-encapsulates and stabilizes a ROS-responsive RNase A prodrug (RNBC) and a GPX-1-targeting DNAzyme with high efficiency. This DZ-RNBC@ZPF nanocomplex, camouflaged with a 4T1 cell membrane, ensures tumour-specific delivery and lysosomal degradation. The acidic environment triggers framework dissolution, releasing Zn²⁺ to activate the DNAzyme. The DNAzyme downregulates GPX-1, amplifying intracellular H₂O₂, which in turn cleaves the NBC group to activate the RNase A prodrug precisely within target cells. This coordinated intracellular cascade-from material degradation to enzymatic ROS amplification and prodrug activation-induces significant apoptosis in 4T1 cells and potently suppresses tumour growth in vivo. Our work establishes ZPF as an enabling platform for the co-delivery of bioactive macromolecules and presents a novel therapeutic strategy based on a synergistic protein prodrug-DNAzyme circuit.