Abstract
Inflammation is an essential contributor to the pathophysiology of numerous diseases, and dysregulation of the involved signaling cascades often culminates in uncontrollable disease progression and, ultimately, chronification. Effectively addressing these disorders is challenging due to their inherent complexity and the need to mitigate inflammation while preserving essential immune functions. Biomaterials have emerged as a promising research area for modulating and resolving inflammatory processes due to their high biocompatibility. Among these, cyclodextrins (CDs), particularly β-CD, are of interest based on their intrinsic anti-inflammatory properties. Chemical modification of the CD base structure to enhance physicochemical properties is a promising strategy to further increase the adaptability of CD-based biomaterials and maximize their therapeutic potential. In this study, we evaluated and characterized the immunomodulatory properties of amphiphilic CD derivatives, which self-assemble into particulate nanostructures, compared to the soluble parent cyclodextrin. Our results demonstrate a significant anti-inflammatory effect of all three CD nanoparticle types in a human macrophage model. These effects surpassed the soluble β-CD control and were specific to each derivative, depending on its underlying physicochemical properties. Notably, we observed significant downregulation of crucial pro-inflammatory markers, along with changes in inflammasome activation and the lipid profile of pro-inflammatory macrophages after CD nanoparticle application. The findings of this study underscore the potential of cyclodextrin-based nanoparticles as versatile biomaterials for treating the complex pathophysiology of various acute and chronic inflammation-associated disorders.