Combining antimiR-25 and cGAMP Nanocomplexes Enhances Immune Responses via M2 Macrophage Reprogramming
Marija Petrovic, Oliwia Majchrzak, Rihana Amreen Mohamed Hachime Marecar, Annick Clara Laingoniaina, Paul R. Walker, Gerrit Borchard, Olivier Jordan, Stoyan Tankov
Abstract
Glioblastoma (GBM) is an aggressive brain cancer with a highly immunosuppressive tumor microenvironment (TME), invariably infiltrated by tumor-associated macrophages (TAMs). These TAMs resemble M2 macrophages, which promote tumor growth and suppress immune responses. GBM cells secrete extracellular vesicles (EVs) containing microRNA-25, which inhibits the cGAS-STING pathway and prevents TAMs from adopting a pro-inflammatory M1 phenotype. This study characterizes antimiR-25/cGAMP nanocomplexes (NCs) for potential therapeutic applications. A particle size analysis revealed a significant reduction upon complexation with antimiR-25, resulting in smaller, more stable nanoparticles. Stability tests across pH levels (4-6) and temperatures (25-37 °C) demonstrated their resilience in various biological environments. Biological assays showed that antimiR-25 NCs interacted strongly with transferrin (Tf), suggesting potential for blood-brain barrier passage. The use of cGAMP NCs activated the cGAS-STING pathway in macrophages, leading to increased type I IFN (IFN-β) production and promoting a shift from the M2 to M1 phenotype. The combined use of cGAMP and antimiR-25 NCs also increased the expression of markers involved in M1 polarization. These findings offer insights into optimizing antimiR-25/cGAMP NCs for enhancing immune responses in GBM.