Nanoparticles-ferrying mitoprotective agents in the aged and reperfused organs

Ischemia-reperfusion injury (IRI) is a major cause of organ dysfunction, with mitochondrial impairment playing a central role. Aging increases susceptibility to IRI through microvascular remodeling, destabilization of mitochondrial membrane potential (ΔΨm), impaired mitochondrial quality control (MQC), and inflammaging, thereby creating biological barriers that limit the efficacy of conventional mitoprotective strategies. Over the past few years, nanoplatforms have evolved from relatively simple targeting systems to multistep and pathology-responsive designs that enhance mitochondrial localization and therapeutic exposure in heart, kidney, brain, and liver IRI models. However, most current strategies have been validated primarily in young models and remain focused largely on oxidative stress modulation. Future studies should prioritize the evaluation of delivery efficiency and long-term functional outcomes in aged models. Integrating MQC-targeted approaches with regulation of the autophagy-lysosome axis may further help overcome age-related constraints and improve translational relevance.