Mitochondria-Targeted Microneedles Reverse Doxorubicin Resistance via Apoptosis-Ferroptosis Synergy

Mitochondrial hyperfunction in doxorubicin (DOX)-resistant breast cancer cells mitigates oxidative stress, contributing to chemoresistance. Here, we present a precise mitochondria-targeted microneedle (MN) delivery strategy incorporating hollow DOX-TPP@ZIF-67 nanoparticles to overcome chemotherapy resistance. This platform was synthesized by loading mitochondria-targeted DOX-TPP into ZIF-67 structures and embedded into fast-dissolving MN patches for localized, organelle-specific drug delivery. Mitochondrial accumulation of DOX-TPP induces ROS overproduction, triggering apoptosis, disrupting cystine-cysteine conversion, depleting glutathione (GSH), and inactivating GPX4. The resulting oxidative imbalance promotes lipid peroxidation and ferroptosis. Additionally, the hydrogen peroxide generated during metabolic reprogramming drives further ferroptosis via the Fenton-like reaction. This approach effectively suppresses the growth of chemoresistant tumors and prolongs survival in DOX-resistant animal models. Our results demonstrate that mitochondria-targeted MN delivery provides a precise strategy to overcome chemoresistance and uncover a mechanism by which enhanced anthracycline efficacy drives the synergistic activation of mitochondrial dysfunction, apoptosis, and ferroptosis.