Intelligent plant exosomes synergize miRNAs and cisplatin for spatiotemporally precise multimodal treatment for TNBC with high safety

Triple-negative breast cancer (TNBC) lacks common receptors and exhibits aggressive behavior, limiting treatment options due to drug resistance and systemic toxicity. TNBC chemotherapy is hindered by poor tumor targeting, drug resistance, and systemic toxicity. Herein, this study presented a cascade targeting exosomal-cisplatin synergistic microneedle nanoplatform (CDDP@RKTExo-MN) as an intelligent wearable therapeutic device for TNBC treatment. Medicinal plant Taxus chinensis derived exosomes (TExo), carrying therapeutic miRNA, was synergized with cisplatin that induced ER stress to trigger a multimodal anti-tumor effects. The cisplatin-loaded TExo was further modified with αvβ3 integrin peptides and an ER-targeting motif for tumor homing and precise subcellular delivery. Leveraging the superficial localization of TNBC, the engineered TExo was integrated into a 3D-printed microneedle patch to construct a closed-loop transdermal delivery system (CDDP@RKTExo-MN). This bioactive architecture ensures precise drug delivery at the tumor site, effectively maximizing therapeutic efficacy while circumventing the systemic off-target toxicity inherent to conventional delivery strategies. CDDP@RKTExo-MN was shown for the cascade targeting capabilities with both cancer cells and their endoplasmic reticulums. By coordinated regulation of MAPK and TNF pathways, the system generated synergistic effects in both significantly amplifying apoptotic signaling and activating immunological protection. In vivo studies conclusively validated its superior tumor suppression efficacy alongside a favorable biosafety. • Engineered medicinal plant exosomes synergize with chemotherapy via transdermal cascade-targeted delivery for safe therapy. • Local microneedle delivery of tumor-ER-targeted TExo enhances anti-tumor effects with low systemic toxicity. • Spatiotemporal drug release improves targeting specificity and reduces off-target effects in cancer therapy.