Membrane Fusion-Mediated Cytosolic Delivery of Threose Nucleic Acids via Homotypic Nanoparticles Overcomes Drug Resistance in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) remains lethal due to its aggressive molecular heterogeneity and drug resistance. We report a biomimetic nanoplatform (PLL/TNA_AKT2@CM NPs) integrating biostable threose nucleic acid (TNA) with a donor-derived cell membranes (CMs) “cloak” for subtype-specific therapy. By complexing TNA_AKT2 antisense oligonucleotides with poly-L-lysine (PLL) and coating them with TNBS-subtype membranes (MDA-MB-468 or MDA-MB-231), we achieve potent homotypic affinity. PLL/TNA_AKT2@468CM NPs exhibited significant enhanced uptake in donor-matched basal-like 1 cells compared to heterotypic TNBC, non-TNBC and normal epithelial cells. Mechanistically, these nanoparticles internalize via a rapid membrane-fusion, bypassing endosomal entrapment for direct cytosolic delivery. This facilitates robust silencing of the AKT2 oncogene, achieving a ∼70% protein knockdown and outperforming conventional transfection reagents. In a drug-resistant MDA-MB-468 xenografts, systemic administration led to superior tumor accumulation, effective AKT2 knockdown, and significant tumor regression via the p21/Caspase-3 apoptotic axis, without systemic toxicity. This versatile “plug-and-play” strategy addresses tumor heterogeneity and endosomal sequestration, providing a transformative paradigm for targeted nucleic acid delivery in refractory cancers. © 2026 The Author(s). Advanced Science published by Wiley-VCH GmbH.