Silk Fibroin in Breast Cancer Therapy: Current Applications and Biological Challenges

Silk fibroin has been extensively investigated as a biomaterial for breast cancer therapy not only for its superior biocompatibility and mechanical properties, but also because it can be processed into distinct delivery systems that provide control over drug incorporation and release profiles. In breast cancer research, this versatility supports both systemic and local drug delivery and allows drug incorporation, retention, and release to be adjusted through material structure and processing. However, its therapeutic performance is strongly influenced by formulation type. β-sheet content, molecular weight, manufacturing conditions, drug–fibroin interactions, and degradation influence drug loading and release. After administration, protein corona formation, cellular uptake, receptor expression, tumor vascular access, and intratumoral heterogeneity can further influence targeting and biodistribution. Protein adsorption may promote recognition and clearance by phagocytic cells or mask targeting ligands, while heterogeneous receptor expression and tumor architecture can limit uniform delivery. Nanoparticles can carry poorly soluble drugs, nucleic acids, and combination therapies, but their efficacy depends on circulation stability and tumor access. Local systems, including hydrogels and films, can prolong exposure at the treatment site and reduce systemic exposure, although their activity remains spatially restricted and their performance varies with material composition and processing. This review therefore examines how silk fibroin structure, processing, formulation, and the biological environment interact to determine therapeutic performance, and critically discusses the limitations affecting reproducibility and potential clinical translation.