Metal-ion-coordinated silk fibroin nanogels for enhanced oral chemotherapy of colorectal cancer.

The efficacy of oral chemotherapy for colorectal cancer (CRC) is hampered by poor drug stability and absorption in the upper gastrointestinal tract, as well as inadequate targeting efficiency at tumor sites. To address these issues, we proposed a simple and biocompatible nanogel, which was co-assembled from chemotherapeutic drug 5-fluorouracil (5-FU), regenerated silk fibroin (SF) as a natural protein carrier, and metal ions (Ni/Cu). The obtained nanogel system exploited the coordination interactions among 5-FU, amino acid residues, and metal ions to form a multifunctional oral nano-drug system with excellent biocompatibility, high delivery efficiency, and superior tumor penetration capacity. Embedding this nanogel in the chitosan/alginate hydrogel enabled it to effectively traverse the gastrointestinal (GI) tract and accumulate at colorectal tumor sites. Furthermore, the multi-stimuli-responsive properties of SF-based nanogel facilitated tumor microenvironment-responsive drug release, while metal ion-mediated chemodynamic therapy synergistically amplified the chemotherapeutic efficacy of 5-FU. This nanogel system provides a facile and translational strategy for improving the therapeutic performance of CRC chemotherapy.