Dual-Ion Crosslinked Alginate Hydrogels for Combined Antioxidant and Anti-Inflammatory Delivery in Colon-Targeted Therapy

Chronic psychological stress disrupts gut homeostasis via activation of the hypothalamic–pituitary–adrenal (HPA) axis, leading to oxidative stress, epithelial damage, and persistent intestinal inflammation. Targeted strategies capable of simultaneously modulating oxidative stress and inflammatory responses are therefore highly desirable for colon-related disorders.

Here, we developed a dual-ion crosslinked sodium alginate (SA) hydrogel for the sustained release of antioxidant mineral-tannic acid nanoparticles (mTNs) under colon-mimicking conditions.

Mannuronic-rich, low molecular weight SA (50-80 kDa; M/G ratio 1.56) was selected to ensure homogeneous nanoparticle incorporation. A controlled pre-gelation step with Ca²⁺ and Zn²⁺ ions was introduced to promote uniform crosslinking and enhance network stability, with Zn²⁺ additionally contributing to epithelial repair and redox regulation.

Composite hydrogels containing 2, 3, and 4 % (w/v) SA and 1 % (w/v) mTNs were prepared and characterized in terms of encapsulation efficiency, mechanical properties, swelling, degradation, and release kinetics in simulated colon fluid. Anti-inflammatory activity was evaluated in LPS-stimulated macrophages by quantifying TNF-α gene expression, while cytocompatibility was assessed in Caco-2 cells.

Encapsulation efficiencies exceeded 80%, and dual ion crosslinking provided tunable mechanical properties comparable to native colon tissue. The composite hydrogels exhibited sustained nanoparticles release over 72 h, while preserving antioxidant activity. Notably, mTN-loaded hydrogels significantly reduced TNF-α expression compared to SA-only controls, confirming an anti-inflammatory effect, with excellent cytocompatibility observed in Caco-2 cells.

Overall, this dual-crosslinked hydrogel platform represents a promising strategy for controlled antioxidant delivery and modulation of stress-related colon inflammation, supporting its potential for colon-targeted therapy.