Silk fibroin-based nanocarriers for anticancer drug delivery: advances, mechanisms, and future perspectives.

Cancer remains a critical global health challenge, with conventional chemotherapy limited by systemic toxicity, poor bioavailability, and lack of tumor specificity. This review comprehensively explores silk fibroin (SF)-a natural, biocompatible, and biodegradable polymer-as a versatile platform for advanced anticancer drug delivery systems. SF's unique structural properties, including amphiphilicity, tunable crystallinity, and abundant functional groups, enable efficient encapsulation of hydrophobic/hydrophilic drugs (e.g., paclitaxel, doxorubicin, curcumin) and facilitate controlled release. We detail SF nanoparticle (NP) fabrication methods (e.g., desolvation, salting-out), alternative delivery forms (hydrogels, microspheres, fibers), and mechanisms for passive (EPR effect) and active targeting (e.g., ligand conjugation to iRGD, LyP-1, HA). Crucially, SF's responsiveness to tumor microenvironment stimuli (pH, redox, temperature, enzymes) enhances site-specific drug release. Key physicochemical parameters-particle size (50-200 nm optimal), surface charge (near-neutral for prolonged circulation), β-sheet content (governing release kinetics), and stability-are analyzed for their impact on therapeutic efficacy. Despite SF's advantages (low immunogenicity, organic solvent-free processing, FDA-approved biocompatibility), challenges persist in batch-to-batch consistency, scalable NP synthesis, and precise control over drug release profiles. Future directions include multifunctional SF hybrids (e.g., magnetic/pH-responsive systems), combinatorial drug loading, and clinical translation to address current chemotherapy limitations. SF-based carriers hold significant promise for enhancing tumor targeting, reducing systemic toxicity, and improving patient outcomes in precision oncology.