In the past decades, the prevalence of neurodegenerative diseases (NDDs) has risen dramatically with the increasing age of human population. Neurodegeneration is a long-term and complex process resulting in the degeneration of neurons. So far, no causative therapy exists, urging the development of methods for the early diagnostics and efficient therapy. In this respect, nanoparticles (NPs) are considered a promising tool due to their efficient blood-brain barrier penetrance and specific interactions with the cellular components. They can localize to mitochondria, nucleus, and autophagosomes and also interact with the cytoskeletal structures as tubulin and Tau protein. Therefore, as mitochondria represent important target for NPs, the therapeutic potential of NPs together with their toxicity to mitochondria has become an emerging topic. In this review, we describe the current knowledge in targeting NPs into mitochondria in relation to Alzheimer’s and Parkinson’s disease. Furthermore, we propose a novel idea how to compensate the compromised mitochondrial functioning without the delivery of NPs into the mitochondrial matrix, specifically by the development of NPs targeting either cytoskeleton or the proteins of mitochondrial motility and fusion-fission machinery. As the latter face cytoplasm, this approach does not require targeting NPs into the mitochondrial matrix. At the same time, it could be a significant step to improve the therapy of NDDs, since the movement, fusion, and fission are necessary for mitochondria to exchange their membrane material, mitochondrial DNA, and to remove the damaged mitochondria.