Engineering Lipid Nanodiscs for Mitochondrial Targeting: From Structural Design to Clinical Potential

Mitochondria play a central role in cellular bioenergetics, apoptosis regulation, and redox homeostasis, making them attractive therapeutic targets in diverse pathologies, including neurodegeneration, ischemia-reperfusion injury, metabolic disorders, and cancer. However, precise delivery of therapeutics to this organelle remains challenging due to its double-membrane barrier, membrane potential-driven selectivity, and the need for subcellular targeting without systemic toxicity. Lipid nanodiscs-synthetic, disc-shaped phospholipid bilayers stabilized by membrane scaffold proteins (MSPs)-have emerged as a modular and structurally uniform platform capable of embedding hydrophobic drugs, membrane proteins, or targeting ligands. Their tunable size, composition, and functionalization with moieties such as triphenylphosphonium (TPP), mitochondria-penetrating peptides (MPPs), or cardiolipin enable high targeting specificity and efficient mitochondrial localization. This review provides a comprehensive analysis of lipid nanodisc structural fundamentals, targeting mechanisms, and bioengineering strategies, supported by quantitative comparative metrics against other mitochondrial delivery platforms. Preclinical evidence demonstrates substantial bioenergetic restoration (ATP ↑ 55-70%), oxidative stress mitigation (ROS ↓ 40-65%), and disease-modifying effects across neurological, cardiovascular, metabolic, and oncological models. Emerging integration of artificial intelligence (AI) and machine learning (ML) into nanodisc design is accelerating optimization of lipid composition, ligand density, release kinetics, and safety profiles, reducing development timelines by over 40%. Despite significant translational promise, challenges remain in large-scale GMP manufacturing, long-term stability, regulatory pathway navigation, and in vivo biodistribution. Addressing these hurdles through advanced protein engineering, stimuli-responsive lipid chemistries, and AI-guided design could position lipid nanodiscs as a cornerstone technology in next-generation precision mitochondrial therapeutics.