Puja Das Karmakar, Masaki Odahara, Keiji Numata
Mitochondria are essential organelles that govern energy metabolism, redox balance, and cell survival; their dysfunction is implicated in a wide range of pathologies, including neurodegenerative disorders, cardiovascular diseases, metabolic syndromes, and cancer. Despite their significance as therapeutic targets, the unique structural and electrochemical properties of mitochondria, particularly the impermeable inner mitochondrial membrane and high membrane potential pose major challenges for the targeted delivery of therapeutic agents. Recent advances in biomaterials have spotlighted peptide-polymer conjugates as versatile platforms, capable of navigating intracellular barriers and achieving precise mitochondrial localization. These hybrid systems combine the physicochemical tunability of polymers with the biofunctionality of peptides, enhancing cellular uptake, endosomal escape, and suborganelle trafficking. The incorporation of stimuli-responsive elements further enables spatiotemporal control of cargo release in response to intracellular cues such as pH shifts, thermal fluctuations, redox gradients, or enzymatic activity. Such systems are especially promising for mitochondrial gene and protein delivery, offering improved selectivity, reduced systemic toxicity, and the potential to restore mitochondrial function under pathological conditions. This review showcases advanced strategies in stimuli-responsive peptide-polymer systems for mitochondria-targeted delivery, highlighting how their smart, responsive functions enable precise, controllable therapeutic interventions and drive the development of next-generation, transformative biomaterials in precision nanomedicine.