Interfacially Integrated DNAzyme-Hydrogel Architectures for Eradicating Postoperative Breast Cancer Residual Disease via Tumor-Anchored Pyroptotic Antigen Amplification

Abstract Postoperative residual disease and insufficient antigenicity after surgical resection are major causes of breast cancer recurrence and metastasis. Pyroptosis enhances antitumor immunity by releasing intracellular antigens but is limited by tight intracellular Ca2+ homeostasis and short reactive oxygen species (ROS) lifespan. This study develops a membrane-confined pyroptotic catalytic platform coupling ROS generation with TRP channel-gated Ca2+ influx to induce pyroptosis and amplify antigenic stimulation in postoperative residual disease. The system comprises a bifunctional DNAzyme (GH) and a CaO2-loaded calcium alginate hydrogel (CaO2-SA). Preoperatively, GH anchors to tumor membranes via nucleolin recognition; postoperatively, CaO2-SA provides sustained H2O2 and Ca2+ at the resection site. Membrane-localized GH catalyzes H2O2 into hydroxyl radicals to oxidatively damage membranes, activate oxidant-sensitive TRP channels, and drive sustained Ca2+ influx. This triggers mitochondrial Ca2+ overload and Caspase-3/GSDME pathway activation, inducing potent pyroptosis. The resultant damage-associated molecular patterns amplify antigenicity, addressing insufficient postoperative immunogenicity in breast cancer.