ABSTRACT 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 Zn 2+ to activate the DNAzyme. The DNAzyme downregulates GPX‐1, amplifying intracellular H 2 O 2 , 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.
Huang et al. (2026) studied this question.