Advanced Targeted Curcumin Delivery Using Spatiotemporally Controlled Nanohybrid Polysaccharide-Based Hydrogel for Ulcerative Colitis Therapy.

In ulcerative colitis (UC), the therapeutic efficacy of nanoparticle (NP)-based drug delivery systems is limited by premature drug release, uptake or degradation of NPs during their passage through the harsh gastrointestinal tract (GIT) environment, poor colon targeting, and rapid NP clearance caused by diarrhea symptoms. This study focused on designing an advanced spatiotemporally controlled nanohybrid hydrogel drug delivery system to overcome these challenges. We developed a pH- and temperature-responsive polysaccharide-based hydrogel composed of chitosan (CS), β-glycerol phosphate disodium salt pentahydrate (GP), hydroxypropyl cellulose (HPC), and collagen type I (Col I), designated as CS/HHPC/Col I-GP. The hydrogel exhibited a dense and uniform porous reticular structure, with an average pore diameter of 127.45 ± 2.22 μm. The equilibrium swelling ratio of the CS/HHPC/Col I-GP was determined to be 32.10 ± 1.11 g/g, indicating excellent swelling capacity and sustained structural stability over 6 h-making it suitable for sustained drug release in the intestinal tract. Then, the prepared curcumin nanoparticles (CurNPs) were encapsulated into the CS/HHPC/Col I-GP hydrogel to form the CS/HHPC/Col I-GP-CurNPs composite. The polysaccharide-based hydrogel shell of the formulation withstood harsh gastrointestinal conditions, enabled targeted adhesion to the colon, and was specifically degraded by colonic enzymes. The CurNPs released in the colon benefit from their negatively charged characteristics, enabling accumulation at the positively charged inflamed sites and achieving sustained Cur release. The results of the gastrointestinal digestion simulation experiment showed that the cumulative release of CS/HHPC/Col I-GP-CurNPs was only 12.33 ± 2.17% in simulated gastric fluid (SGF) and reached 96.91 ± 1.98% in simulated colonic fluid (SCF) after 60 h. Cell and animal experimental data confirmed that the formulation significantly alleviated colitis symptoms by modulating the repolarization of pro-inflammatory M1 macrophages to anti-inflammatory M2 phenotypes and deactivating the TLR4/MyD88/NF-κB pathway. Furthermore, the integrity of the intestinal mucosal barrier and the gut microbiota were enhanced. This study provides a promising strategy for the oral drug treatment of UC.