A Mito-CoQ10-TPP Nanocarrier Hybrid Enhances the Therapeutic Efficacy of Mitochondrial Transplantation in Alzheimer’s Disease

Abstract Mitochondrial dysfunction is an early pathological aspect of Alzheimer’s disease (AD) that promotes oxidative stress, leading to amyloid β-plaque formation and neurofibrillary tangles. Thus, targeted mitochondrial therapy and mitochondrial transplantation have emerged as promising therapeutic strategies. However, excessive oxidative stress and neuroinflammation in the microenvironments of the AD brain limit the functional and stable integration of transplanted mitochondria. In this study, we have engineered a Mito-CoQ10-TPP hybrid nanocarrier by conjugating triphenylphosphonium (TPP), a lipophilic cation, with Coenzyme Q10 (CoQ10) and localized it to mitochondria isolated from healthy cortical brain cells. This nanocarrier hybrid was administered via a single intravenous (IV) dose to streptozotocin (STZ)-induced AD in mice. A comprehensive evaluation of mitochondrial function, amyloid burden, neuroinflammation, apoptosis, biogenesis, and behavior revealed that CoQ10-TPP conjugation significantly improved the mitochondrial transplantation efficacy in the amelioration of AD. Thus, conjugating the antioxidant CoQ10 with mitochondrial transplantation significantly improved the overall therapeutic efficacy, indicating the use of the Mito-CoQ10-TPP hybrid nanocarrier as a promising therapeutic strategy.