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.