Abstract

Triple-negative breast cancer (TNBC) remains a therapeutic challenge due to its aggressive behavior and lack of targeted treatments. We developed Sor@AKAExo, a bioinspired exosomic nanoplatform that utilizes Anoectochilus roxburghii-derived exosomes both as a nanotherapeutic delivering endogenous miRNAs and as a carrier for incorporating and delivering ferroptosis inducer sorafenib. Functionalization with the AS1411 aptamer enables tumor targeting, while conjugation with the KLA peptide facilitates mitochondrial localization, achieving spatiotemporal codelivery of both miRNAs and sorafenib. Accordingly, Sor@AKAExo synergistically induces ferroptosis and apoptosis through sorafenib-induced GPX4 suppression, lipid peroxidation, mitochondrial dysfunction, and caspase-3 activation. These effects are further enhanced by exosomal miRNA-mediated downregulation of the MAPK pathway and upregulation of the IL-17 and cholesterol metabolism pathways. This dual death-initiating mechanism disrupts the redox homeostasis, overcomes metabolic resistance, and remodels the immunosuppressive tumor microenvironment. In vivo, Sor@AKAExo exhibits potent antitumor efficacy with excellent biosafety. This work presents a bioinspired plant-derived exosome-based immunotherapy that synergistically activates both ferroptosis and apoptosis circuits with precise spatiotemporal control, addressing the obstacles of absent active targeting, limited drug delivery efficacy, and adaptive drug resistance in TNBC treatment.