In this work, we report on the construction of TME-responsive immunostimulatory nanomedicine based on dsDNA loaded by biocompatible DMONs with small particle size and large pore size, which provide efficient protection and delivery of dsDNA for triggering intratumoral IFN-Is production to activate innate sensing, enabling the enhanced anti-tumor immunotherapy with marked therapeutic efficacy and biosafety. Here, IFNA1 is linked to neoplasm.