Cellulose nanocrystals (CNCs) are rod-like nanoparticles derived from natural cellulose sources through acid hydrolysis, typically using sulfuric or hydrochloric acid. This process removes amorphous regions of cellulose, leaving behind highly crystalline domains with diameters ranging from 5 to 20 nm and lengths between 100 and 500 nm. Their unique properties, including high surface area, mechanical strength, and biodegradability, make them attractive for biomedical applications, particularly in colon-targeted drug delivery. A key advantage of CNCs is their resistance to human digestive enzymes but susceptibility to degradation by colonic microbiota, enabling site-specific drug release.

The resistance of CNCs to human enzymes stems from the absence of cellulases in the human gastrointestinal tract. Humans lack the enzymatic machinery to hydrolyze the β-1,4-glycosidic bonds in cellulose, which prevents premature degradation of CNC-based carriers in the stomach and small intestine. Studies confirm that CNCs remain structurally intact when exposed to gastric acid, pepsin, pancreatic enzymes, and bile salts, ensuring that conjugated drugs are protected during transit through the upper gastrointestinal tract. This stability is critical for achieving targeted delivery to the colon, where microbial action triggers degradation.

In contrast, colonic microbiota possess a diverse array of cellulolytic enzymes, including endoglucanases, exoglucanases, and β-glucosidases, which collectively break down cellulose into short-chain fatty acids and gases. Bacterial species such as Bacteroides, Ruminococcus, and Clostridium are particularly efficient at metabolizing cellulose. When CNCs reach the colon, microbial enzymes cleave the crystalline structure, releasing any conjugated drugs. The rate of degradation depends on factors like crystallinity, surface chemistry, and the presence of microbial populations. Higher crystallinity generally slows degradation, whereas surface modifications can tailor the release kinetics.

The extraction of CNCs via acid hydrolysis plays a crucial role in determining their properties. Sulfuric acid hydrolysis introduces sulfate ester groups on the CNC surface, imparting colloidal stability in aqueous media but potentially altering biodegradability. Hydrochloric acid hydrolysis produces CNCs with fewer surface charges, which may degrade more readily in the colon due to reduced electrostatic repulsion with microbial enzymes. The choice of acid and hydrolysis conditions must balance stability during transit with controlled degradability in the colon.

Drug conjugation to CNCs often involves ester linkages, which are stable in the upper gastrointestinal tract but cleavable by microbial enzymes. Carboxyl groups on oxidized CNCs can be esterified with drug molecules containing hydroxyl or carboxylic acid functionalities. For example, anti-inflammatory drugs like ibuprofen or chemotherapeutic agents like 5-fluorouracil have been conjugated to CNCs via ester bonds. These linkages remain intact in acidic and neutral pH conditions but undergo hydrolysis by bacterial esterases or amidases in the colon. The drug release profile can be fine-tuned by adjusting the degree of substitution and the length of spacer molecules between the CNC and the drug.

A significant advantage of CNCs over non-polysaccharide colon-targeting systems is their inherent biocompatibility and natural origin. Synthetic polymers like Eudragit or azoreductase-sensitive coatings rely on pH-dependent dissolution or reductive cleavage, which can be less predictable due to interindividual variability in gut pH and microbiota composition. CNCs, being derived from plant cellulose, are inherently recognized and processed by colonic bacteria without the need for synthetic triggers. This reduces the risk of incomplete drug release or unintended systemic absorption.

Moreover, CNCs avoid the drawbacks associated with non-polysaccharide systems, such as potential toxicity from synthetic polymer degradation products or limited adaptability to diverse drug molecules. Their high surface area allows for efficient drug loading, while their nanoscale dimensions facilitate mucoadhesion and prolonged residence time in the colon. Studies demonstrate that CNC-based carriers exhibit superior targeting efficiency compared to conventional systems, with minimal drug leakage in the upper GI tract and sustained release in the colon.

The degradability of CNCs by colonic microbiota also aligns with sustainable drug delivery objectives. Unlike non-biodegradable carriers, CNCs are fully metabolized into harmless byproducts, eliminating concerns about long-term accumulation. The short-chain fatty acids produced during microbial degradation, such as acetate, propionate, and butyrate, may confer additional therapeutic benefits by modulating colonic pH and supporting gut health.

In summary, cellulose nanocrystals offer a robust platform for colon-targeted drug delivery due to their unique enzymatic resistance and microbiota-dependent degradability. Acid hydrolysis extraction methods define their structural and surface properties, while ester-based drug conjugation ensures controlled release in the colon. By leveraging natural polysaccharide metabolism, CNCs circumvent the limitations of synthetic targeting systems, providing a biocompatible and efficient alternative for therapeutic delivery. Future research may explore the impact of CNC surface modifications on microbial degradation rates and the optimization of drug loading strategies for clinical translation.