2. Academic Validation
  3. Mitochondria-Targeted Microneedles Reverse Doxorubicin Resistance via Apoptosis-Ferroptosis Synergy

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

  • ACS Nano. 2025 Jul 1;19(25):23315-23333. doi: 10.1021/acsnano.5c06302.
Tianshu Hao 1,  Hanze Guo 2,  Chenyuan Wang 1,  Shisuo Jing 1,  Wen Zhang 1,  Yongnian Zeng 1,  Jinxuan Hou 3,  Zhiyin Song 4 2,  Wei Li 1 4 5
Affiliations

Affiliations

  • 1 Department of Stomatology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
  • 2 College of Life Sciences, Wuhan University, Wuhan 430072, Hubei, China.
  • 3 Department of Thyroid & Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
  • 4 TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China.
  • 5 Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
PMID: 40534228 DOI: 10.1021/acsnano.5c06302
Abstract

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.

Keywords

ROS; drug-resistant breast cancer; microneedle; organelle-specific drug delivery; targeting mitochondria.

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