Hybrid Magnetic Nanovesicles for Synergistic Cancer Therapy by Manipulating Intratumoral RNA Interference and Fenton Chemistry

RNA interference has garnered significant interest as a type of nucleic acid therapeutics. MicroRNA (miRNA)-mediated mRNA modulation and gene therapy have yielded promising progress. However, clinical application is impeded by low delivery efficiency and insufficient targeting specificity. We herein develop a hybrid membrane-based delivery system with a magnetic core and spatially isolated functional nucleic acid strands. Due to the hybrid lipid bilayer, CD47-mediated immune evasion and galectin-3-mediated homologous targeting facilitate effective delivery of nucleic acids and magnetic nanomaterials. The membranes effectively protect these antitumor reagents during transportation. After internalization inside tumor sites, the strand displacement reaction between the nucleic acids successfully releases miR-200c, which stimulates inflammatory cytokine secretion and modulates apoptotic cytokine expression. Meanwhile, the acidic microenvironment dissociates Fe 2+ from the magnetic core and initiates the Fenton reaction to amplify cytotoxic oxidative damage. The two pathways thereby confer robust antitumor efficacy with synergistic effects, which have great potential for future clinical translation.