An Engineering‐Editable Hybrid Membrane‑Camouflaged DNA Origami Drug Enables Checkpoint Blockade and Immune Activation for Triple‐Negative Breast Cancer Immunotherapy

ABSTRACT The clinical response to immunotherapy in triple‐negative breast cancer (TNBC) is often limited by the immunosuppressive microenvironment, immune cell exhaustion, and multidrug resistance. Through a high‐throughput screen of 2,500 FDA‐approved drugs using a three‐dimensional tumor organoid platform, we identified thonzonium bromide (THO) as an inducer of gasdermin D (GSDMD)‐mediated pyroptosis, which results in the release of damage‐associated molecular patterns (DAMPs) to activate antitumor immunity. To achieve targeted delivery, we designed a core–shell‐structured biomimetic nanoparticle (THO/AMT‐si NP) consisting of a core formed by tetrahedral DNA (TDN NPs) constructed using DNA origami technology, which is loaded with THO and P‐gp siRNA, and an outer layer coated with a programmatically designed hybrid membrane (AREP). These findings indicate that THO/AMT‐Si NPs can effectively target TNBC tumors, convert “cold” tumors into “hot” tumors by inducing pyroptosis in cancer cells, reverse immune cell exhaustion, and simultaneously overcome cancer cell multidrug resistance, thereby achieving synergistic inhibition of tumor growth and metastasis. In summary, this biomimetic nanomedicine enhances immunotherapy for TNBC by combining synergistic cascade targeting, immune checkpoint blockade, and thermosis‐mediated immune activation.