Targeting Cancer Mitochondria with Stimuli-Responsive Nanocarriers: Emerging Strategies for Precision Oncology

Mitochondria are central regulators of cancer cell survival, metabolism, and therapy resistance, making them a promising yet underutilized target in modern oncology. Internal stimuli such as altered redox balance, elevated reactive oxygen species (ROS), and acidic pH uniquely characterize the tumor microenvironment, providing a distinct trigger for smart drug delivery. Internal stimuli-responsive nanocarriers have emerged as an innovative strategy to achieve spatiotemporal control of drug release while selectively homing to subcellular organelles such as mitochondria. This review outlines the multifaceted role of mitochondria in cancer progression, chemoresistance, and metastasis, and highlights the unique biochemical hallmarks of cancer cells that facilitate targeted delivery. We further explore recent advances in the development of pH-, redox-, ROS-, and enzyme-sensitive nanocarriers that exploit these internal cues to localize chemotherapeutic agents specifically to cancerous mitochondria. We also compare their advantages and limitations with conventional chemotherapy and other targeting approaches. Additionally, translational challenges, limitations, and future directions including vesicle-mediated mitochondria transfer are discussed, aiming to reduce systemic toxicity while improving therapeutic efficacy.