Lipid Nanoparticles for Driving Macrophages to Promote Proinflammatory Cytokine Upregulation

Macrophages play an essential role in human health and disease. They are functionally versatile cell types with a wide range of functions and can multitask by modulating their phenotypes. Macrophage polarization to the desired state is an excellent therapeutic strategy for various diseases, and nanomedicines are used as drug delivery platforms to modulate macrophages selectively. In this context, the development of nanoparticles (NPs) with inherent bioactivity has great potential and is an unmet need. To this end, we designed and synthesized a series of lipids with single-tail and heterocyclic amine head groups with intrinsic bioactivity and developed them into a library of LNP formulations. We studied their bioactivity using proinflammatory cytokine production in macrophages as a model system. Our study demonstrated that lipid nanoparticles (LNPs) can interact with and enter macrophages. Furthermore, the lipid head groups in LNPs activated toll-like receptors (TLRs), leading to the upregulation of proinflammatory cytokines. Additionally, these studies highlighted that the composition of LNPs and physicochemical properties govern their bioactivity toward inducing proinflammatory cytokines. Overall, our approach to developing LNPs with intrinsic properties has several applications in the field of nanomedicine. In addition, the ability of LNPs to modulate macrophages will receive more attention in developing therapeutics where macrophage modulation is a therapeutic target.