Translating a miRNA Signal into Physical Immunomodulation via Programmed DNA Network Assembly on Mitochondria

Precision immunotherapy is critically hampered by the nonspecific toxicity of cGAS-STING pathway agonists. We overcome this fundamental barrier with a programmable DNA nanomaterial that operates as a logic-gated theranostic agent at the organelle level. Our nanodevice targets mitochondria and uses an integrated catalytic circuit to decipher the presence of oncogenic microRNA-21 (miR-21). Upon positive identification, it triggers the in situ architectural assembly of a physically disruptive DNA network on the mitochondrial surface. This targeted structural stress inflicts profound membrane damage, weaponizing the tumor cell's own mitochondrial DNA as a precision-guided agonist to ignite a powerful, localized STING-mediated immune assault. This strategy provides a dual function, enabling amplified diagnostic imaging of its molecular trigger while orchestrating the profound suppression of both primary and metastatic tumors in vivo with undetectable systemic toxicity. This work establishes a new design principle for intelligent therapeutics and defines a new therapeutic paradigm, the direct conversion of a fleeting molecular signal into a stable, physical, and immunomodulatory structure, forging a new frontier for dynamic materials in precision medicine.