Injectable self-healing oxidized pectin and carbohydrazide-modified gelatin hydrogels for curcumin-loaded zein nanoparticle delivery in antioxidant therapy

The design of drug delivery systems (DDS) for efficient and sustained in situ antioxidant treatment is demanded in regenerative medicine applications. DDS, based on nanoparticle-loaded hydrogels, are promising advanced drug delivery platforms to achieve prolonged release and targeted bioactivity. Herein we developed innovative and sustainable injectable hydrogels based on oxidized pectin (PDA) and carbohydrazide-modified gelatin (G-CDH) for the release of curcumin-loaded zein nanoparticles (CurZNPs) for mitigating cell oxidative stress. CurZNPs, produced by nanoprecipitation, exhibited high encapsulation efficiency, sustained curcumin release, and strong antioxidant and anti-inflammatory activities. PDA/G-CDH hydrogels with three different PDA : G-CDH ratios were prepared by double physical and chemical crosslinking, through calcium ions internally released from CaCO3 and Schiff base formation between PDA and G-CDH functional groups, respectively. PDA/G-CDH hydrogels showed rheological tunability, depending on the degree of pectin oxidation (2.5 mol%: PDA2.5 and 5 mol%: PDA5). Hydrogels with a balanced aldehyde-to-amine ratio, specifically the PDA2.5/G-CDH (70 : 30) and PDA5/G-CDH (50 : 50) formulations, were selected based on their superior stability in physiological conditions, consistent with effective crosslinking. Such compositions also exhibited injectability through shear thinning behaviour, and self-healing by restored mechanical integrity after stress, and supported human fibroblast viability and attachment. CurZNPs-loaded PDA/G-CDH hydrogels showed prolonged curcumin release, antioxidant activity by restoring fibroblast viability after induced oxidative damage, and anti-inflammatory properties with RAW 264.7 macrophages. In conclusion, injectable PDA/G-CDH hydrogels were efficient and biocompatible DDS for antioxidant treatment through controlled CurZNPs release.