Macrophage Polarization-Inducible Cholesterol Lipid-Assisted Nanoparticles Prime Systemic Antitumor Immunity

Nanomaterials with intrinsic biological activity can directly participate in disease treatment, emerging as a pivotal focus in the development of next-generation therapeutics. In this study, we synthesized a library of cholesterol lipids bearing diverse tertiary amine head groups via a straightforward amidation reaction, then co-assembled them with amphiphilic polyethylene glycol-poly (lactic-co-glycolic acid) (PEG- b -PLGA) to formulate hybrid nanomaterials. Notably, the cholesterol derivative A3-Chol-formulated nanomaterials (A3-Chol@NP) polarized macrophages toward the pro-inflammatory M1 phenotype and enhanced phagocytosis of tumor cells. At the mechanistic level, A3-Chol@NP has been observed to preferentially interact with mitochondria in macrophages to produce mitochondrial reactive oxygen species (mtROS). This, in turn, activates ROS-NF-κB-iNOS and ROS-IRF5-IL-23 pathways, which have been identified as key factors in the macrophage polarization to M1-type. In the B16-F10 mouse melanoma model, A3-Chol@NP efficiently suppressed tumor growth via macrophage-mediated immunotherapy and completely blocked tumor progression when combined with anti-PD-L1 antibody.