Cyclodextrins as Active Therapeutic Agents

Abstract

Cyclodextrins (CDs) have traditionally been recognized as excipients that enhance solubility and stability of drugs. However, growing evidence shows that CDs themselves can act as active therapeutic agents. Their unique supramolecular properties enable them to interact with biological membranes, mobilize cholesterol, and modulate immune responses. This review highlights four therapeutic areas where CDs demonstrate particular promise. First, in gene and mRNA therapy, cationic CD derivatives form nanoparticles that protect nucleic acids, promote endosomal escape, and achieve targeted delivery. Second, in neurodegenerative disorders such as Niemann–Pick type C and Alzheimer’s disease, hydroxypropyl-β-CD facilitates cholesterol clearance and reduces pathological lipid accumulation. Third, in detoxification, the γ-CD derivative sugammadex exemplifies a clinically approved agent that encapsulates neuromuscular blockers to reverse anesthesia. Finally, CDs have emerged as safe vaccine adjuvants, inducing robust systemic and mucosal immunity with reduced IgE responses compared to alum. Together, these examples illustrate a paradigm shift: CDs are not only versatile excipients but also active molecules with direct therapeutic effects. Future translation will require careful optimization of safety, scalability, and regulatory compliance, but CDs are poised to contribute meaningfully to next-generation medicines.

Introduction

Cyclodextrins were first isolated in the late 19th century, but it was not until the latter half of the 20th century that their potential in pharmaceutical formulations was fully recognized [1]. Over the ensuing decades, these cyclic oligosaccharides have transitioned from being viewed solely as solubilizing agents and stabilizers to being acknowledged as compounds with intrinsic biological activity. Initially, cyclodextrins attracted attention in pharmaceutical science because they were able to improve the aqueous solubility and stability of poorly soluble drugs. These effects are not intrinsic properties of cyclodextrins themselves but rather the direct result of their ability to form noncovalent host–guest inclusion complexes with a wide variety of drug molecules [2,3,4,5].

This ability is largely attributed to their distinctive toroidal structure, which presents a hydrophilic exterior and a hydrophobic cavity, thereby allowing them to encapsulate lipophilic compounds in a reversible manner. As our understanding of cyclodextrin chemistry deepened, researchers began to uncover that these host–guest interactions are not merely passive processes. Rather, they can actively mediate biological responses at both cellular and systemic levels.

For example, recent studies have demonstrated that cyclodextrins are able to modulate the composition of lipid rafts within cell membranes—a process that can influence receptor clustering and ultimately trigger specific intracellular signaling pathways [6,7].

This discovery has broadened the scope of cyclodextrin applications beyond drug solubilization to include direct therapeutic interventions. In parallel, significant progress has been made in the chemical modification of cyclodextrins. A recent editorial by Kfoury et al. (2025) highlighted the revival of cyclodextrins as active pharmaceutical ingredients, with examples in cholesterol modulation, rare diseases, and viral infections [8].

While that article provided a concise perspective, the present review builds upon this foundation by offering a comprehensive and systematically structured synthesis of cyclodextrins’ therapeutic roles, including gene and mRNA delivery, vaccine adjuvants, microbiome modulation, oncology applications, and detailed safety and toxicity considerations [8].

Techniques such as methylation, hydroxypropylation, and sulfobutylether substitution have been employed to generate derivatives with markedly enhanced aqueous solubility, reduced toxicity, and improved pharmacological profiles [9,10,11]. These modifications not only optimize the inclusion complex formation but also allow for a more targeted interaction with biological membranes and receptors. As a result, cyclodextrin derivatives are now being explored as active agents in diverse therapeutic applications, including gene therapy—where they serve as carriers for nucleic acids—and as modulators of immune responses, thereby offering new strategies for vaccine development and immunotherapy [12,13]. The discovery of such properties has prompted renewed interest in the broader therapeutic potential of CDs in various fields, including gene therapy, neurodegenerative diseases, detoxification, and immunomodulation.

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Table 4. Summary of preclinical studies on cyclodextrin-mediated gene delivery, including derivative type, genetic cargo, target cells, and key outcomes. Abbreviations: HP-β-CD = hydroxypropyl-β-cyclodextrin.

The following excipients are mentioned in the study besides other: β-Cyclodextrin

Pirvu, A.S.; Varut, R.-M.; Trasca, D.-M.; Stoica, G.A.; Radivojevic, K.; Carmen, S.; Arsenie, C.C.; Popescu, C. Cyclodextrins as Active Therapeutic Agents: Beyond Their Role as Excipients. Pharmaceuticals 2025, 18, 1592. https://doi.org/10.3390/ph18101592

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