Smart Hydrogel Releases Drug Only Where Colitis Inflammation Runs Hot

Ulcerative colitis is one of medicine’s stubborn mysteries: a chronic inflammatory disease of the intestine that currently has no known cure. Its global footprint is expanding fast, with prevalence in North America now exceeding 400 cases per 100,000 people and an incidence in the United Kingdom of 12.6 per 100,000 person-years. Patients endure bloody diarrhea, rectal bleeding, abdominal pain, anemia, and cramping in cycles of flare and remission that can last a lifetime. Existing drugs, including 5-aminosalicylic acid, corticosteroids, immunosuppressants, and biological agents, achieve clinical remission in only about 40 percent of cases, and even then they mostly suppress symptoms rather than restoring the gut microbiome or the damaged intestinal barrier. Oral, injected, and rectal routes of delivery all suffer from low efficiency and poor targeting specificity, meaning much of the drug never reaches the diseased tissue. Against this backdrop, a research team has now engineered an ingeniously responsive delivery system that aims to put powerful anti-inflammatory therapy exactly where it is needed and nowhere else.

Writing in the journal Materials Today Bio, researchers led by Chen Zhang, Shanying Han, and Ruiyao Zhou describe a reactive oxygen species-responsive, small-molecule self-assembled nanocarrier integrated into a hydrogel, which they call HA/MPC@B. The central insight is that inflamed colonic tissue is chemically distinctive: it is bathed in abnormally high concentrations of reactive oxygen species, the volatile molecules that drive oxidative stress and destroy the protective gastrointestinal mucosal layer. Rather than fighting this harsh chemistry, the team exploits it as a trigger. The system is built around a borate ester group derived from pinacol 4-hydroxyphenylborate, a chemical bond that remains stable in ordinary physiological conditions but cleaves selectively when it encounters the elevated reactive oxygen microenvironment of a colitis lesion. This means the drug stays locked away during its journey through the stomach and healthy intestine and is released preferentially at the site of disease.

The construction of the nanocarrier itself is a feat of molecular design accomplished in three steps. First, the researchers coupled pinacol 4-hydroxyphenylborate with 1,1′-carbonyl diimidazole, producing an intermediate with non-toxic, removable imidazole as the only by-product. Second, under catalysis by 4-dimethylaminopyridine, this intermediate was covalently crosslinked with D-mannose, a sugar that serves double duty as a hydrophilic anchor and, crucially, as a targeting ligand. The resulting amphiphilic molecules self-assemble spontaneously in water into nanoparticles roughly 160 to 170 nanometers in diameter, with a hydrophilic outer shell of mannose polyhydroxy groups and amide bonds surrounding a hydrophobic core of phenyl rings and ether linkages. Fourier-transform infrared spectroscopy, ultraviolet-visible spectroscopy, and proton nuclear magnetic resonance collectively confirmed each stage of synthesis, tracking the disappearance and emergence of characteristic peaks for hydroxyl, carbonyl, boronate ester, imidazole, and sugar-ring groups.

Into these self-assembled spheres, the team loaded berberine, a natural plant-derived compound with well-documented anti-inflammatory, antibacterial, barrier-repairing, and microbiota-regulating effects, but notoriously poor solubility and bioavailability. Dynamic light scattering showed the loaded nanoparticles had a mean diameter of about 160 nanometers and a surface zeta potential of minus 33.13 millivolts. Encapsulation efficiency reached 77.93 plus or minus 2.87 percent, with a drug loading capacity of 23.76 plus or minus 0.67 percent, figures that underscore the exceptional loading power of small-molecule self-assembly. Transmission electron microscopy revealed a higher electron density in the interior of loaded particles compared with empty ones, a direct visual signature that berberine sat packed inside. Stability testing in simulated gastric, intestinal, and colonic fluids showed the particles held together through intestinal and colonic transit, yet visibly disassembled in simulated gastric fluid and, tellingly, in colonic fluid spiked with hydrogen peroxide to mimic the inflamed colon.

The final layer of the system is a hybrid hydrogel of hyaluronic acid and hyaluronate methacrylate, a biodegradable and biocompatible matrix that is injectable and shear-thinning, meaning its viscosity drops under force so it flows easily yet reforms a stable gel afterward. Scanning electron microscopy showed the composite formed an interconnected three-dimensional porous skeleton whose irregular pores facilitate diffusion of the nanoparticles and strengthen their adhesion to the intestinal wall. In drug release assays across 48 hours, the hydrogel held cumulative berberine release below 20 percent in neutral buffer, simulated gastric fluid, simulated intestinal fluid, and simulated colonic fluid. But in colonic fluid supplemented with 0.1 millimolar hydrogen peroxide, mimicking the high-reactive oxygen environment of inflamed tissue, cumulative release jumped to 52.02 plus or minus 4.11 percent. The hydrogel also delayed release compared with bare nanoparticles, acting as a depot that guards against premature leakage while the payload travels to the colon.

Safety came first in the evaluation. Cytotoxicity testing on Caco-2 intestinal epithelial cells showed no significant loss of viability at berberine-equivalent concentrations up to 1.0 milligram per milliliter, the concentration chosen for all subsequent experiments. Hemolysis assays demonstrated a hemolysis rate below 5 percent, meeting the accepted criterion for biomedical materials, and live/dead staining over 72 hours showed living cells dominating every treatment group at every time point. Targeting was verified with striking clarity in RAW264.7 macrophages. A fluorescent mannose probe was avidly internalized by the cells, but when the researchers pre-blocked the mannose receptor with free mannose or competed with unlabeled nanoparticles, fluorescence plummeted; flow cytometry quantified mean fluorescence falling from 71.9 in the probe-only group to 31.5 in the competition group. This proved the mannose-decorated nanoparticles specifically recognize macrophage mannose receptors, which are overexpressed on inflammatory immune cells at lesion sites.

The therapeutic action proved multimodal. In macrophages stimulated with lipopolysaccharide to mimic a hyperinflammatory state, the loaded nanoparticles and the full hydrogel suppressed the pro-inflammatory M1 phenotype, marked by CD86, and restored the anti-inflammatory M2 phenotype, marked by CD206. Gene expression analysis showed tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 all falling, while the anti-inflammatory interleukin-10 rebounded above control levels. The system also scavenged reactive oxygen species broadly, neutralizing hydroxyl radicals, hydrogen peroxide, and superoxide anions in cell-based assays. In DSS-injured Caco-2 monolayers, treatments accelerated cell migration in scratch-wound assays, reduced FITC-dextran leakage across the epithelium, and restored the tight junction proteins ZO-1 and Claudin-1 along with their messenger RNA, evidence that the damaged intestinal barrier was genuinely being rebuilt, not merely soothed.

In vivo results in a mouse model of acute colitis, induced by dextran sulfate sodium in drinking water, confirmed the design logic. Mice receiving the hydrogel by oral gavage showed the best weight recovery among all treatment groups, higher survival, reduced disease activity index scores, suppressed splenomegaly, and reversal of colon shortening. Fluorescence imaging with Cy5.5-labeled formulations revealed the difference decisively: free dye vanished within hours, bare nanoparticles leaked fluorescence throughout the digestive tract within four hours after gastric acid exposure, but the hydrogel-protected formulation produced intense, sustained fluorescence in the inflamed colon from 4 to 36 hours after administration, because the crosslinked matrix shields the nanoparticles from stomach acid until they reach their target. Histology showed the lowest pathological scores in the hydrogel group, myeloperoxidase staining revealed sharply reduced neutrophil infiltration, and serum FITC-dextran levels confirmed restored barrier integrity. A healthy control group given the hydrogel showed no adverse changes, indicating good biosafety at the therapeutic dose.

Perhaps most remarkably, 16S rRNA sequencing and transcriptomic analysis traced the therapy’s effects deep into biology. Colitis had disrupted the gut microbiome, enriching pro-inflammatory genera such as Helicobacter, Escherichia-Shigella, Rothia, and Moraxella while depleting beneficial taxa like Muribaculaceae and Alloprevotella; the hydrogel treatment reversed this dysbiosis, restoring microbial profiles that clustered with healthy controls. Transcriptome sequencing of colonic tissue found 385 genes upregulated and 196 downregulated after treatment, with cell proliferation and epithelial regeneration genes such as Lgr5, Agr2, and Cldn8 rising while pyroptosis and inflammatory genes including Casp4, Nos2, Il17a, and Gsdmd fell. Gene ontology analysis showed suppression of NF-kappaB and NLRP3 inflammasome pathways, confirmed by quantitative PCR showing reduced Tlr4 and Rela and increased Nfkbia. Together, these layers of evidence, from molecular cleavage chemistry to microbiome ecology, present HA/MPC@B as an intelligent, multifunctional platform that treats ulcerative colitis through targeted delivery, on-demand drug release, antioxidant and immune modulation, barrier repair, and microbiota remodeling, offering a compelling blueprint for clinical translation.

Subject of Research: A ROS-responsive small-molecule self-assembled nanocarrier-integrated hydrogel for targeted treatment of ulcerative colitis

Article Title: ROS-responsive small-molecule self-assembled nanocarrier-integrated hydrogels for ulcerative colitis treatment

Article References: ROS-responsive small-molecule self-assembled nanocarrier-integrated hydrogels for ulcerative colitis treatment. (n.d.). https://doi.org/10.1016/j.mtbio.2026.103684

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103684

Keywords: ulcerative colitis, ROS-responsive drug delivery, nanocarriers, hydrogel, berberine, hyaluronic acid, macrophage polarization, intestinal barrier, gut microbiota, NF-kappaB signaling, oxidative stress, drug targeting