Abstract
Inflammation plays a critical role in the pathophysiology of many diseases, and dysregulation of the involved signaling cascades often culminates in uncontrollable disease progression and, ultimately, chronic manifestation. Addressing these disorders requires balancing inflammation control while preserving essential immune functions. Cyclodextrins (CDs), particularly β-CD, have gained attention as biocompatible biomaterials with intrinsic anti-inflammatory properties, and chemical modification of their backbone offers a promising strategy to enhance their physicochemical properties, adaptability, and therapeutic potential. This study evaluated and characterized the immunomodulatory effects of amphiphilic CD derivatives, which self-assemble into nanoparticles, compared to soluble parent β-CD. In a human macrophage model, CD nanoparticles demonstrated superior anti-inflammatory activity, with derivative-specific effects tied to their physicochemical properties, surpassing the soluble β-CD control. Alongside the downregulation of key pro-inflammatory markers, significant reductions in inflammasome activation and changes in lipid profiles were observed. 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.