Targeted ‘Tfam’ activation and ‘Mitoq’ therapy for pearson syndrome

Abstract

This study investigates a novel therapeutic strategy for Pearson syndrome by combining Mitochondrial Transcription Factor A (TFAM) activation with the antioxidant MitoQ in a dual-loaded nanoparticle system. Pearson syndrome, a mitochondrial disorder characterized by severe multi-systemic effects due to mitochondrial DNA deletions, necessitates targeted interventions aimed at restoring mitochondrial function and reducing oxidative damage. (1) In this study, we developed a dual therapeutic platform encapsulating siRNA targeting TFAM alongside MitoQ, aiming to simultaneously enhance mito- chondrial biogenesis and neutralize reactive oxygen species (ROS). The nanoparticles were successfully formulated with two distinct particle populations, concentrated at 97 nm and 132.7 nm, with an average particle size of 116.3 nm, ensuring optimal cellular uptake and mitochondrial target- ing. The surface charge, measured as +53.5 mV, indicated strong colloidal stability and facilitated intracellular delivery. Both the siRNA and MitoQ demonstrated high loading efficiencies, achieving 93.4% and 94.4% encapsu- lation, respectively, with an overall system encapsulation efficiency of 92.3%. The therapeutic efficacy of the system was further supported by functional studies. ROS levels were significantly reduced by 2.1-fold with MitoQ treat- ment alone, while the combined siRNA-MitoQ system achieved a 1.9-fold re- duction, highlighting the synergistic effect of antioxidant activity and TFAM modulation. Additionally, ATP production, a critical indicator of mitochondrial function, was elevated by 3.4-fold in cells treated with the dual-loaded nanoparticles, demonstrating the system’s potential to restore energy pro- duction in mitochondria-compromised cells. These results suggest that this dual-targeted nanoparticle system, leveraging the complementary actions of siRNA-induced TFAM activation and MitoQ’s antioxidant properties, presents a promising therapeutic approach for miti- gating mitochondrial dysfunction and oxidative stress in Pearson syndrome.