Abstract
Physiochemical properties of nanoparticles, such as their size and chemical composition, dictate their interaction with professional phagocytes of the innate immune system. Macrophages, in particular, are key regulators of the immune microenvironment that heavily influence particle biodistribution as a result of their uptake. This attribute enables macrophage-targeted delivery, including for phenotypic modulation. Saccharide-based materials, including polyglucose polymers and nanoparticles, are efficient vehicles for macrophage-targeted delivery. Here, we investigate the influence of particle size on cyclodextrin nanoparticle (CDNP) uptake by macrophages and further examine the receptor-mediated interactions that drive macrophage-targeted delivery. We designed and synthesized CDNPs ranging in size from 25 nm to >100 nm in diameter. Increasing particle size was correlated with greater uptake by macrophages in vitro. Both scavenger receptor A1 and mannose receptor were critical mediators of macrophage-targeted delivery, inhibition of which reduced the extent of uptake. Finally, we investigated the cellular bioavailability of drug-loaded CDNPs using a model anti-inflammatory drug, celastrol, which demonstrated that drug bioactivity is improved by CDNP loading relative to free drug alone. This study thus elucidates the interactions between the polyglucose nanoparticles and macrophages, thereby facilitating their application in macrophage-targeted drug delivery that has applications in the context of tissue injury and repair.