Calcium retinoate nanoparticle mediated microglial polarization to regulate inflammatory microenvironment for therapy of neuroinflammatory disease

Abstract

Microglia-mediated neuroinflammation can lead to progressive neuronal damage, accelerating the development of neurodegenerative changes or existing neurological disorders. Regulating microglial activation to reshape the inflammatory microenvironments has increasingly become a promising therapeutic target for the treatment of neurological diseases. Retinoic acid, a natural small-molecule compound, holds potential neuroprotective and immunomodulatory properties. However, its poor water solubility poses a challenge to its bioavailability. In this study, calcium retinoate nanoparticles (Ca-RA NPs) were proposed and synthesized through a coordination reaction between retinoic acid molecules and calcium ions, which were proved to be easily endocytosed by microglia and rapidly decomposed into small molecule/ion storms in lysosomes. In vitro experimental results demonstrated that Ca-RA NPs can inhibit lipopolysaccharide (LPS)-induced M1 polarization of microglia while promoting their polarization toward the M2 phenotype. Furthermore, the mechanism underlying the anti-inflammatory effects of Ca-RA NPs on microglia is closely associated with the inhibition of mitogen-activated protein kinase and NF-κB signaling pathways. Notably, cell co-culture experiments revealed that Ca-RA NPs mediated immune microenvironment can indirectly promote neuronal differentiation of neural stem cells (NSCs) by selectively modulating microglial M1/M2 polarization. In vivo experimental results further demonstrated that Ca-RA NPs can not only alleviate the local inflammatory microenvironment but also promote the neuronal differentiation of endogenous NSCs to repair damaged neurons, thereby improving the behavioral functions of LPS-induced neuroinflammatory mice. These findings highlight the potential of Ca-RA NPs as a promising therapeutic approach for neuroinflammation by targeting microglia.

Keywords

calcium retinoate nanoparticle / inflammatory microenvironment / microglial polarization / neuroinflammatory disease

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RIGHTS & PERMISSIONS

2025 The Author(s). BMEMat published by John Wiley & Sons Australia, Ltd on behalf of Shandong University.