Macrophage cell therapy enabled by interleukin-4 mRNA-loaded lipid nanoparticles to sustain a pro-reparative phenotype in inflammatory injuries

The use of macrophage cell therapies is limited by their tendency to change phenotype in response to external cues in situ. Here we demonstrate that an optimized lipid nanoparticle (LNP) formulation effectively delivers IL4 mRNA to human and murine primary macrophages, resulting in rapid transfection, IL-4 secretion, and reparative phenotype modulation. In a model of murine volumetric muscle loss, adoptively transferred macrophages pre-treated with IL4-LNPs maintained a reparative phenotype for at least one week, despite the inflammatory injury microenvironment. IL4-LNP-treated macrophages also promoted a reparative phenotype in endogenous macrophages and supported muscle repair outcomes, including increased vascularization, fiber size distribution, and remodeling of the scaffold. T cell subtype in the muscle or the draining lymph node was not affected. The novel strategy established here may facilitate the control and use of macrophage cell therapies for other applications in regenerative medicine.