β-cyclodextrin-based multifunctional carriers for colon-targeted drug delivery: advances in hydrogel systems and mucoadhesive strategies

Oral drug delivery to the colon remains a formidable challenge due to the harsh conditions of the upper gastrointestinal tract, including variable pH, enzymatic degradation, and limited mucosal permeability. β-Cyclodextrin (β-CD), a cyclic oligosaccharide with a hydrophobic cavity and hydrophilic exterior, offers a promising approach to overcome these barriers by forming stable inclusion complexes that protect sensitive drugs and modulate their release profile. This review explores the use of native and chemically modified β-CDs as functional carriers for colonic drug delivery, with a focus on hydrogel-based systems, mucoadhesive derivatives, and microbiota-responsive formulations. A critical review of over two decades of literature was conducted to evaluate the design, performance, and pharmacokinetic benefits of β-CD-loaded systems for intestine-specific therapeutic delivery. Evidence shows that β-CD hydrogels loaded with anti-inflammatory drugs, chemotherapeutics, and poorly soluble molecules achieve pH-sensitive, sustained drug release with improved mucosal adhesion and enhanced bioavailability. Thiolated β-CDs and hydroxypropyl derivatives improve the intestinal residence time and facilitate permeation across the mucus barrier. In additionf, S-protected thiolated β-CDs and NAC/arginine-modified β-CDs exhibit superior mucoadhesion and epithelial absorption, offering prolonged gastrointestinal retention. Formulations incorporating microbiota-triggered release mechanisms exhibit targeted activation in the colon due to fermentation/degradation of β-CDs by colonic Bacteroides, thereby reducing the systemic side effects. The manuscript also critically examines the application of β-cyclodextrin and its derivatives in advancing colon-targeted drug delivery through pH-responsive hydrogels synthesized via structural modifications, such as thiolation and hydroxypropylation that significantly enhance mucoadhesion, residence time, and drug permeation across intestinal barriers. The integration of β-CD with biopolymers and smart release triggers enables a controlled, site-specific therapeutic release with reduced systemic toxicity and improved pharmacokinetics. Overall, β-CD-based carriers enable multifunctional, site-specific delivery to the colon through a combination of physicochemical stabilization, mucoadhesion, and enzymatic responsiveness. Their application spans both small molecules and biologics, positioning β-CD as a foundational scaffold in the development of next-generation oral therapeutics for gastrointestinal disorders.