A Mechanistic Investigation of Modified Curcumin-Nanoparticle-Loaded Hybrid Hydrogel against Breast Cancer

Curcumin (Cur) is a natural polyphenol known for its anti-inflammatory, antioxidant, antimicrobial, and anticancer properties. Nonetheless, its clinical application is severely limited by poor aqueous solubility, rapid degradation, and inadequate cellular internalization. To overcome these barriers, we developed structurally optimized curcumin nanoparticles (CurNPs) with enhanced physicochemical stability and bioavailability and evaluated their anticancer performance using a 3D-printed gelatin/sodium alginate/nanocellulose hydrogel tumor model. Utilizing a three-dimensional (3D) breast tumor model, we systematically evaluated the antitumor efficacy of CurNPs and explored their mechanisms of action. The CurNPs markedly suppressed tumor cell proliferation, migration, and invasion and induced cell cycle arrest and apoptosis in both MCF-7 and MDA-MB-231 cell lines. Molecular analysis revealed significant downregulation of β-catenin (0.39-fold and 0.59-fold) and Cyclin D1 (0.84-fold and 0.56-fold), alongside upregulation of pro-apoptotic Bax (2.4-fold and 2.3-fold) and epithelial marker E-cadherin (18.8-fold and 11.6-fold). These molecular alterations are consistent with phenotypes of cell cycle arrest and apoptosis and suggest potential interactions with multiple signaling networks. This study demonstrates the promising potential of CurNPs as a localized bioresponsive platform for breast cancer therapy, validated through both 2D and 3D in vitro models. Furthermore, in vivo evaluation using a breast tumor-bearing mouse model demonstrated that CurNPs markedly inhibited tumor growth and reduced tumor volume compared with free curcumin. No significant systemic toxicity was observed, indicating the favorable biocompatibility of CurNPs. Our findings lay the foundation for further translational research and future clinical evaluation.