Anti-inflammatory effects of cyclodextrin nanoparticles enable macrophage repolarization and reduce inflammation

Discover Nano Research Anti‑inflammatory effects of cyclodextrin nanoparticles enable macrophage repolarization and reduce inflammation Felix E. B. Brettner1 Maike Windbergs1 · Stefanie Gier1 · Annika Haessler1 · Jonas Schreiner1 · Sarah Vogel‑Kindgen1 · Received: 7 June 2024 / Accepted: 13 December 2024 © The Author(s) 2024  OPEN 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. Keywords Nanoparticles · Amphiphilic cyclodextrins · Macrophages · Inflammation · Inflammasome · Lipidomic profiling · Immunomodulation · Anti-inflammatory effect Abbreviations ASC Apoptosis‑associated speck‑like protein containing a CARD CD Cyclodextrin CDC Native β-CD control cDNA Complementary deoxyribonucleic acid CD-NPs Amphiphilic cyclodextrin nanoparticles CDOC6 Heptakis-6-O-hexanoyl-β-cyclodextrin CDOC12 Heptakis-6-O-lauroyl-β-cyclodextrin CDSC6 Heptakis-(6-deoxy-6-hexylthio)-β-cyclodextrin DAPI 4′,6-Diamidino-2-phenylindole Supplementary Information The online version contains supplementary material available at https://doi.org/10.1186/s11671-024- 04175-6. * Maike Windbergs, | 1Institute of Pharmaceutical Technology, Goethe-University Frankfurt, Max‑von‑Laue‑Straße 9, 60438 Frankfurt am Main, Germany. Discover Nano (2024) 19:211 | https://doi.org/10.1186/s11671-024-04175-6 Vol.:(0123456789) Research Discover Nano (2024) 19:211 | https://doi.org/10.1186/s11671-024-04175-6 DLS Dynamic light scattering ELISA Enzyme-linked immunosorbent assay ELS Electrophoretic light scattering IFNγ Interferon‑γ IL Interleukin LPS Lipopolysaccharides LXR pathway Liver-X-receptor pathway M1 Manders’ coefficient fraction 1 mRNA Messenger ribonucleic acid MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay MΦ0 Resting macrophages MΦ1 Activated, pro‑inflammatory macrophages NLRP3 NLRP family pyrin domain containing 3 NP Nanoparticle PBS Phosphate‑buffered saline PC1/2 Principal component 1/2 PCA Principal component analysis PCR Polymerase chain reaction PDI Polydispersity index PMA Phorbol‑12‑myristate‑13 acetate RNA Ribonucleic acid RPMI Roswell Park Memorial Institute 1640 RT Room temperature RT-qPCR Real time quantitative PCR SEM Scanning electron microscopy TNFα Tumor necrosis factor α 1 Introduction Inflammation is a complex physiological response of the immune system to harmful stimuli, such as tissue injury or infection by pathogens. It is characterized by highly coordinated physiological and biochemical events involving various immune cells, chemical mediators, and molecular pathways that aim to protect the body, eliminate exogenous harms, and facilitate tissue regeneration. Thus, inflammation plays a crucial role in establishing cellular homeostasis and is an integral function of the human body [1–3]. While an essential defense mechanism, excessive or chronic inflammation can lead to severe organ or tissue damage and contribute to the development of multiple disorders, including autoimmune diseases as well as neurodegenerative, cardiovascular, and rheumatic conditions [4–7]. Current strategies to advance therapeutic approaches involve applying suitable biocompatible materials, and the identification and design of biomaterials that can directly interact with cells and tissue of the inflamed microenvironment is in high demand [8–12]. As cells of the innate immune system, macrophages are particularly attractive targets for immune modulation via biomaterials due to their unique role in tissue repair and homeostasis regarding all stages of inflammation [13–16]. In this context, naturally derived cyclodextrins (CDs) are of considerable interest, as current research data hints at intrinsic anti-inflammatory properties of native β-CD and water-soluble CD derivatives [17, 18]. In general, CDs harbor distinctive stereochemical features due to the circular α−1,4 glycosidic linkage of D-glucopyranose units, forming a truncated cone shape with the primary hydroxyl groups at the narrow rim and the secondary hydroxyl groups at the wider edge [19, 20]. This molecular structure results in a relatively hydrophobic inner cavity and a hydrophilic outer surface, which enables the formation of inclusion complexes trapping various small molecules and even larger biomacromolecules into a hydrophobic core [21–25]. Naturally occurring CDs are classified as α-, β-, and γ-CDs depending on the number of connected D-glucopyranose with six, seven, and eight sugar units, respectively [26–28]. In addition to their remarkable molecular features, native hydrophilic CDs are non-toxic and hold the GRAS ("Generally Recognized as Safe") status [29]. All these characteristics facilitate the use of CDs in various fields, including pharmaceutical and biotechnological sciences, as well as food, cosmetics, and agriculture. Especially β-CDs are widely used to enhance the solubility, stability, or bioavailability of poorly soluble drugs without toxic side effects [21, 30, 31]. Moreover, the unique molecular structure of Vol:.(1234567890) Discover Nano (2024) 19:211 | https://doi.org/10.1186/s11671-024-04175-6 Research CDs is predestined for chemical alteration through the addition of functional groups, selectively altering the physico- and biochemical characteristics of the resulting derivatives. Chemically modifying the hydrophilic core structure by grafting aliphatic chains, for example, renders the CD molecules amphiphilic, initiating the surfactant-free self-assembly into vesicles, micelles, or nanoparticles (NPs) [32–35]. Via adaption of the chain length or further chemical alterations, the characteristics of these supramolecular structures (...truncated)