ROS-responsive MnO2 mesoporous hydrogel to modulate liver-muscle crosstalk and mitigate NAFLD-associated sarcopenia via exosomal miR-582-5p delivery

<b>Background:</b> The interrelation between non-alcoholic fatty liver disease (NAFLD) and sarcopenia has emerged as a significant concern due to its systemic impact on metabolic health. However, therapeutic approaches targeting the liver-muscle axis remain underdeveloped. Oxidative stress and inflammatory pathways are key mediators of this crosstalk, exacerbating disease progression. This study aims to develop a reactive oxygen species (ROS)-responsive MnO₂ mesoporous PD (HA) hydrogel to modulate this axis and investigate its therapeutic efficacy in NAFLD-associated sarcopenia. <b>Methods:</b> MnO₂ mesoporous PD (HA) hydrogels were synthesized with ROS-sensitive properties and characterized for rheological, fluorescence, and conductivity responses. A HepG2-C2C12 co-culture model mimicked the NAFLD-muscle wasting interplay, while high-fat diet (HFD)-induced NAFLD mouse models were used for in vivo evaluations. Cellular stress markers, exosomal miR-582-5p signaling, and atrogenic pathways were assessed using immunofluorescence, qRT-PCR, and histological analyses. <b>Results</b>: Pathway analysis of HFD-induced NAFLD showed upregulation of lipid metabolism and inflammatory signaling, promoting muscle atrophy via exosomal miR-582-5p. The MnO₂ mesoporous hydrogel significantly reduced oxidative stress and inflammation in the HepG2-C2C12 co-culture. In vivo, hydrogel implantation in HFD mice mitigated hepatic fibrosis, reduced ROS accumulation, preserved muscle fiber integrity, and downregulated atrogenic markers. <b>Conclusions:</b> The MnO₂ mesoporous PD (HA) hydrogel presents a dual-targeting therapeutic strategy for NAFLD and sarcopenia by attenuating oxidative stress and modulating liver-muscle axis signaling. These findings provide a foundation for innovative interventions targeting metabolic comorbidities.