Tampering with microglia-mediated neuroinflammation by means of DNA nanostructures

Neuroinflammation is one of the characteristic hallmarks of ALS and most other neurodegenerative diseases. In particular, microglial cells, the immune cells of the central nervous system, play a crucial role in this process and therefore in neurodegeneration. In fact, in early phases of chronic neurodegenerative diseases, microglia acquire an M2 phenotype, which is neuroprotective, while in advanced phases, microglia acquire the M1 phenotype, that turns out to be neurotoxic. The mechanisms that regulate the spreading of activation from activated microglial cells to non-activated ones is still unknown, nevertheless exosomes seem to be involved. We have previously demonstrated that activation of microglia stimulates the release of exosomes, also changing their content [1]. In Atomic Force Microscopy, the possibility to apply localized forces and to measure the resulting behavior of the probed system allows for the nanomechanical characterization of biological systems, including live cells. We have performed a nanomechanical analysis of live microglial cells both in resting an in activated cellular systems. We have shown that the inherent morphological changes also imply a measurable change in the mechanical properties of these cells, providing a measurement of activation alternative to end-point molecular characterizations. As we have proved that microglia can spontaneously internalize tetrahedron-like DNA selfassembled nanostructures, we endowed such nanostructures with functional elements designed to interact with cellular RNAs that are involved in the microglial activation process. We recorded a reduction in the specific content of intracellular RNA, and we also verified a reduced expression of one of the protein biomarkers of neuroinflammation as a consequence of the uptake of the DNA nanostructures. The effects of DNA nanostructures in modulating the nanomechanics of activated microglial cells can be assessed next.