A Supramolecular Nanoengine Generates Nanomechanical Force on Demand for Precise Cytosolic Delivery of Anti‐miRNAs and Synergistic TNBC Therapy

Abstract Although anti‐microRNA (miRNA) is capable of silencing target miRNA and regulating multiple mRNAs in diverse signaling pathways, RNA medicines still encounter numerous challenges, especially in terms of poor delivery, inefficient endo/lysosomal escape, and suboptimal treatment. Herein, we have developed a carrier‐free supramolecular nanoengine, AMGA (anti‐miRNA/GEM 2 ‐Azo), which significantly enhances the cytosolic delivery of anti‐miRNA without requiring light irradiation, thereby facilitating precise targeting and synergistic chemo‐gene therapy for triple‐negative breast cancer (TNBC). AMGA can be rapidly internalized by cancer cells and specifically generate nanomechanical force to promote the efficient escape of anti‐miRNAs from the endo/lysosome to the cytoplasm, simultaneously downregulating miR‐21 and miR‐10b. In comparison to Lipofectamine 2000, AMGA demonstrated superior efficacy in inhibiting the proliferation, migration, and invasion of cancer cells. Significantly, AMGA exhibited profound antitumor and gene silencing effects in an orthotopic human TNBC mouse model. This novel supramolecular nanoengine presents a promising strategy for cytosolic delivery of anti‐miRNAs.