Biodegradable microparticles promote anti-inflammatory innate immune memory through a size- and mTOR-dependent process

Emerging evidence demonstrates that innate immune cells can maintain a nonspecific memory not only in response to microbe-associated ligands such as β-glucan but also synthetic biomaterials, nano- and microparticles. This creates an opportunity to leverage biomaterials that can establish favorable innate immune responses and memory for therapeutic applications. In this study, we identify particle size as a critical physical determinant influencing both acute macrophage activation and long-term innate immune memory. Specifically, biodegradable poly(lactic-co-glycolic acid) (PLGA) particles in the 1 µm to 2 µm size range promoted an anti-inflammatory phenotype and enhanced oxidative phosphorylation in bone marrow-derived macrophages through a process dependent on mTOR signaling. In contrast to the well-documented pro-inflammatory innate immune training seen with microbial stimuli such as β-glucans, exposure of macrophages to 1 µm to 2 µm PLGA particles promoted a durable anti-inflammatory reprogramming, marked by elevated IL-10 and IL-1 receptor (IL-1Ra) antagonist secretion upon secondary stimulation, and metabolic rewiring. Moreover, bone marrow from mice injected with PLGA particles in this size range were reprogrammed to upregulate IL-1Ra and IL-10 secretion upon a restimulation, which persisted up to 1 wk after injection. These findings uncover how the physicochemical properties of polymeric nanoparticles differentially modulate innate immune cells and regulate the induction of innate training.