Wearable microneedle-delivered homotypic exosomes sensitize ferroptosis for triple-negative breast cancer therapy

Triple-negative breast cancer (TNBC) is clinically intractable due to its aggressiveness and lack of targeted therapies. While inducing ferroptosis via RSL3 shows promise, its efficacy is limited by tumor redox adaptation and systemic toxicity. Mono-target approaches are insufficient against TNBC’s adaptive survival mechanisms. To overcome this, we developed a bioinspired wearable platform, R@CTE-M. This platform co-delivers RSL3, a glutathione peroxidase 4 (GPX4) inhibitor, and bioactive endogenous Tripterygium wilfordii-derived exosomal miRNAs (TE-miRs) using engineered Tripterygium wilfordii-derived exosomes (TExos) camouflaged with homologous 4T1 cancer cell membranes. This construct is integrated into a 3D-printed porous microneedle patch for localized transdermal delivery. The homologous membrane enables 4T1 tumor-targeted delivery. R@CTE-M markedly inhibited tumor growth and showed a favorable preliminary biocompatibility profile in the 4T1 tumor-bearing mouse model. Mechanistically, TE-miRs disrupt redox homeostasis, activate JNK/FoxO-mediated apoptosis, and downregulate SLC7A11, thereby sensitizing cells to RSL3-triggered ferroptosis. This coordinated multi-pathway attack enhances the ferroptotic response, overcoming intrinsic resistance and reducing systemic toxicity. R@CTE-M represents a novel, wearable exosome-based multi-target therapy, offering a transformative and translatable strategy for TNBC treatment.