Purpose <p>There is a current surge in the global occurrence of neurodegenerative diseases (ND), a collection of age-related diseases highly associated with mitochondrial dysfunction. Mitochondria supply cellular energy (depleted in ND), mediate cell death (which is premature in ND), and rescue cells from the unfolded protein response (accumulation of misfolded proteins is associated with ND). Mitochondrial Network Enhancing (MiNE) nanoparticles (NPs) have been designed to correct mitochondrial dysfunction in ND by increasing mitochondrial networks and increasing the fusion of mitochondria to the endoplasmic reticulum (ER).</p> Methods <p>Nanoparticles encapsulating a pro-Mitofusin 2 (MFN2) peptide were synthesized and characterized for size, zeta potential, and drug loading efficiency. MFN2 mediates mitochondrial fusion and mitochondrial-ER fusion. Live cell microscopy of MiNE NP and control treated primary hippocampal neurons and NIH3T3 fibroblasts at 60X was performed and images were processed using mitochondrial network analysis software to quantify changes in mitochondrial networks. Mitochondrial-ER co-localization studies were performed along with an unfolded protein response study and an oxidative phosphorylation assay.</p> Results <p>Treatment with MiNE NPs increases mitochondrial networks and increases mitochondrial-ER co-localization. MiNE NPs increase the cellular capacity for oxidative phosphorylation which could increase energy efficiency in ND. Importantly, MiNE NPs protect against the unfolded protein response which could decrease the accumulation of misfolded proteins in ND.</p> Conclusion <p>MiNE NPs are a novel translational nanomedicine for treating ND by targeting the intersection of mitochondria and the ER. These preliminary studies of MiNE NPs validate further evaluation of MiNE NPs as a promising treatment for ND and as an anti-aging strategy.</p> Graphical Abstract <p></p>