Microglia have become a therapeutic target of many inflammation-mediated diseases in the central nervous system (CNS). Recently, microRNA (miRNA) has been proposed as an important regulator of immune responses. Specifically, miRNA-129-5p has been shown to play critical roles in the regulation of microglia activation. We have demonstrated that biodegradable poly (lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) modulated innate immune cells and limited neuroinflammation after injury to the CNS. In this study, we optimized and characterized PLGA-based NPs for miRNA-129-5p delivery to utilize their synergistic immunomodulatory features for activated microglia modulation. A series of nanoformulations employing multiple excipients including epigallocatechin gallate (EGCG), spermidine (Sp), or polyethyleneimine (PEI) for miRNA-129-5p complexation and miRNA-129-5p conjugation to PLGA (PLGA-miR) were utilized. We characterized a total of six nanoformulations through physicochemical, biochemical, and molecular biological methods. In addition, we investigated the immunomodulatory effects of multiple nanoformulations. The data indicated that the immunomodulatory effects of nanoformulation, PLGA-miR with the excipient Sp (PLGA-miR+Sp) and PEI (PLGA-miR+PEI) were significant compared to other nanoformulations including naked PLGA-based NP. These nanoformulations promoted a sustained release of miRNA-129-5p and polarization of activated microglia into a more pro-regenerative phenotype. Moreover, they enhanced the expression of multiple regeneration-associated factors, while alleviating the expression of pro-inflammatory factors. Collectively, the proposed nanoformulations in this study highlight the promising therapeutic tools for synergistic immunomodulatory effects between PLGA-based NPs and miRNA-129-5p to modulate activated microglia which will have numerous applications for inflammation-derived diseases.
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