Endogenous and exogenous tumor-related microRNAs (miRNAs) are considered promising tumor biomarkers and tumor therapeutic agents. In this work, we propose a miRNA self-responsive drug delivery system (miR-SR DDS), which enables the association between endogenous and exogenous miRNAs, so as to achieve a smart responsive and synergistic drug delivery. The miR-SR DDS consists of DNA-miRNA hybrids of let-7a and the complementary DNA of miR-155, which was packaged in exosomes. In response to the overexpressed miR-155 in breast cancer cells, the hybrids disintegrate and release let-7a and the complementary DNA of miR-155 to inhibit the expression of HMGA1 and relieve the inhibition of SOX1, respectively. Under the dual-targeted gene regulation, results show that the growth, migration and invasion of breast cancer cells can be synergistically inhibited through the Wnt/β-catenin signaling pathway. The concept and successful practice of the miR-SR DDS can be used as a reference for the development of miRNA drugs.