Nanoengineered RNA delivery systems for gene therapy in intestinal fibrosis.

Intestinal fibrosis is a major complication of inflammatory bowel disease, particularly Crohn's disease, leading to strictures, luminal narrowing, and tissue remodeling. Despite advances in anti-inflammatory therapies, no approved pharmacological treatments are available to prevent or reverse established fibrosis, highlighting an urgent unmet clinical need. Fibrogenesis is driven by interconnected molecular pathways, including TGF-β/SMAD, Wnt/β-catenin, and inflammatory signaling networks, which promote epithelial-to-mesenchymal transition, fibroblast activation, and excessive extracellular matrix deposition. Recent evidence highlights the critical regulatory role of gene regulatory networks and noncoding RNAs, particularly microRNAs, in modulating fibrotic responses. However, the clinical translation of RNA-based therapeutics remains limited by biological and pharmacological barriers, including RNA instability, poor tissue specificity, and inefficient gastrointestinal delivery. To address these challenges, nanoengineered delivery systems have emerged as promising platforms to protect RNA cargo, improve cellular uptake, and enable targeted intestinal delivery. Lipid nanoparticles, polymeric nanocarriers, and extracellular vesicle-based systems have shown encouraging preclinical performance by improving RNA bioavailability, reducing off-target effects, and modulating key fibrotic pathways in experimental models of intestinal fibrosis. This review highlights the molecular mechanisms underlying intestinal fibrosis, current gene- and RNA-based therapeutic strategies, advances in nanocarrier engineering, and the manufacturing and regulatory considerations that influence clinical translation. Together, the available evidence indicates that the integration of RNA therapeutics with rationally designed nanocarriers represents a promising strategy to overcome current delivery limitations. Nevertheless, successful clinical translation will require standardized formulations, robust preclinical validation, scalable manufacturing processes, and precision medicine approaches to enable safe and effective antifibrotic therapies for patients with intestinal fibrosis.