Organelle-Specific Drug Delivery Systems in the Treatment of Rare Mitochondrial and Peroxisomal Disorders: A Frontier in Precision Nanotherapeutics

Rare mitochondrial and peroxisomal disorders represent a group of devastating, genetically inherited metabolic diseases characterized by organelle dysfunction, disrupted cellular homeostasis, and profound clinical heterogeneity. Current treatment strategies are largely palliative, with conventional pharmacotherapies demonstrating limited efficacy due to poor intracellular targeting and systemic toxicity. Organelle-specific drug delivery has emerged as a transformative approach in precision medicine, offering enhanced therapeutic precision, reduced off-target effects, and improved bioavailability at the subcellular level. This review explores the pathophysiological landscape of mitochondrial and peroxisomal disorders, highlighting the molecular underpinnings and clinical manifestations of key syndromes such as MELAS, Leigh syndrome, Zellweger spectrum disorders, and X-linked adrenoleukodystrophy. We systematically discuss organelle-targeting strategies, including lipophilic cations, mitochondria-penetrating peptides, peroxisomal targeting signals, and ligand-conjugated nanocarriers. Furthermore, we evaluate nanocarrier platforms such as liposomes, dendrimers, polymeric nanoparticles, and biomimetic systems that have been engineered for organelle-directed therapies. Preclinical and clinical progress in targeting these organelles using antioxidant drugs, gene delivery vectors, and enzyme-loaded nanoparticles is examined, along with existing translational and regulatory challenges. Finally, the review delves into emerging trends such as CRISPR/Cas-based genome editing, artificial organelles, and AI-driven nanomedicine design, outlining a forward-looking roadmap for organelle-specific therapeutics in ultra-rare disease contexts.