Preclinical study demonstrates that photo-crosslinked gelatin-cellulose nanofibers trigger colon-specific 5-ASA release in colitic mice, suggesting a targeted oral therapy for ulcerative colitis.
Background Conventional ulcerative colitis (UC) therapies are limited by low colonic bioavailability and systemic side effects due to premature drug release in the upper gastrointestinal tract. To overcome these issues, we developed an orally administrable, photo-crosslinked nanofiber composed of coumaroyl-modified gelatin (Cm-Gel) and coumaroyl-modified cellulose nanocrystals (Cm-CNC) for colon-targeted delivery of 5-aminosalicylic acid (5-ASA). Results The nanofibers was fabricated by electrospinning a Cm-Gel: Cm-CNC composition followed by UV-induced photodimerization, forming a stable photo-crosslinked network. Spectroscopic and microscopic analyses confirmed the electrostatic interactions between Cm-Gel and Cm-CNC, as well as the successful photodimerization of coumaroyl groups. The Cm-Gel: Cm-CNC nanofibers exhibited minimal 5-ASA release under acidic conditions, while release was markedly enhanced under colonic pH (6.5–7.5). This release was further enhanced in the presence of sulfatase enzyme (a colonic enzyme) due to network dissociation and triggered on-demand drug release. This was attributed to the incorporation of Cm-CNC, which significantly improved mechanical strength, network integrity, and swelling capacity, contributing to sustained and controlled release of the payload due to photodimerization. At non-cytotoxic doses, the calcein-loaded Cm-Gel: Cm-CNC nanofibers showed significantly higher cellular uptake than calcein-loaded Cm-Gel only nanofibers. Intracellular trafficking studies further demonstrated effective lysosomal localization of the nanofibers, while DCFH-DA analysis confirmed significant reduction of intracellular oxidative stress, and hemolysis testing verified excellent hemocompatibility. In a DSS-induced colitis mouse model, in vivo fluorescence imaging revealed that the DiR-loaded Cm-Gel: Cm-CNC nanofibers achieved significantly higher intestinal uptake compared with free DiR alone. Similarly, 5-ASA-loaded nanofibers effectively alleviated DSS-induced colonic inflammation, reduced histopathological damage as confirmed by H&E staining and tight-junction protein (Occludin, Claudin-1, and ZO-1) immunohistochemical staining, and suppressed pro-inflammatory cytokines (IL-6 and TNF-α) in the blood serum. These therapeutic outcomes surpassed those of free 5-ASA and unloaded nanofibers. Conclusions The orally administrable photo-crosslinked Cm-Gel: Cm-CNC nanofibers provides complete biodegradability and targeted, sulfatase enzyme- and pH-responsive release of 5-ASA in the colon. Its strong anti-inflammatory efficacy, biocompatibility, and controlled-release behaviour highlight its promise as a safe, colon-specific, multi-stimuli-responsive drug-delivery platform for ulcerative colitis.
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Joy et al. (2026) studied this question.
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