Targeting neuroinflammation in Parkinson's disease: Immunomodulatory effects of a hyaluronic acid-based nanoreinforced hydrogel loaded with GDNF and mesenchymal stem cells

• The anti-inflammatory effects of a hydrogel loaded with GDNF and mesenchymal stem cells (MSCs) were characterized. • The hydrogel reduced nitric oxide (NO) production in BV2 microglial cells stimulated with lipopolysaccharide (LPS). • The hydrogel downregulated the expression of pro-inflammatory pathways. • Conversely, it upregulated the expression of anti-inflammatory pathways. • The hydrogel shows promise as a potential treatment for widespread neuroinflammation. Like other neurodegenerative disorders, Parkinson's disease is marked by widespread neuroinflammation, which may contribute to its etiology and is a key component of its progression. Consequently, anti-inflammatory strategies, which can incorporate regenerative and cell therapy components, are promising therapeutic candidates for the management of the disease. To this end, we have developed a supramolecular hydrogel (HG) based on modified hyaluronic acid that combines nanoencapsulated GDNF (NPs GDNF), a potent neurotrophic factor with a less well-studied anti-inflammatory potential, and human mesenchymal stem cells (MSCs). We have evaluated the anti-inflammatory effect of the HG by quantifying the NO produced by a murine microglia cell line against LPS. In addition, we have corroborated these functional results by transcriptomic analyses, where we have also been able to delve deeper into the mechanisms by which the HG exerts this anti-inflammatory effect. We have observed that both HG components (GDNF and MSCs) and the combination of all of them (HG-NPs GDNF-MSCs) are able to decrease NO production in microglia insulted with LPS. Furthermore, we have been able to corroborate these results at the transcriptional level, where HG was able to decrease most of the pathways commonly associated with inflammation, such as interferon regulators or the interleukins IL-1 or TNF-α. In conclusion, the developed HG was able to reduce inflammation in a murine microglial cell line, both transcriptionally, with the suppression of pro-inflammatory pathways, and functionally, with a reduction in nitric oxide production.