Mitochondria-targeted nanomedicine for cancer therapy: Targeting strategies, therapeutic mechanisms, and translational challenges

Abstract

Mitochondria are central regulators of cellular energy metabolism, redox homeostasis, and programmed cell death, making them highly attractive targets for cancer therapy. Rapid advances in nanotechnology have enabled the rational design of mitochondria-targeted nanomedicines for subcellularly precise drug delivery. At present, mitochondrial targeting is mainly achieved by surface modification with lipophilic cations or functional peptides. Nanoparticles (NPs) equipped with these moieties can preferentially accumulate in tumor-cell mitochondria and enhance antitumor efficacy through multiple mechanisms, including disruption of redox balance, interference with energy metabolism, damage to mitochondrial structure, and induction of immunogenic cell death. These systems may also reduce systemic toxicity and help overcome therapeutic resistance. However, a comprehensive framework for the rational design of mitochondria-targeted nanoparticles remains lacking. In this review, we summarize current design strategies for mitochondria-targeted nanoparticles, discuss their multidimensional antitumor mechanisms, and highlight recent advances in their applications in cancer therapy. We further examine the major challenges related to targeting efficiency, biosafety, and clinical translation. This review aims to provide a useful reference for the development of next-generation mitochondria-targeted nanotherapeutics with improved precision and efficacy.