Precision design of ferritin nanocages: tumor-targeted delivery, multi-mechanism synergistic therapy and clinical translational challenges.

OBJECTIVE

To elucidate the application potential of ferritin nanocarriers in targeted cancer therapy, particularly for central nervous system (CNS) tumors (e.g. glioblastoma), focusing on their structural advantages, drug-loading capacity, targeting strategies, and emerging therapeutic directions.

REVIEW SIGNIFICANCE: Ferritin, leveraging its natural biocompatibility, biodegradability, and unique cage-like structure, is a highly promising drug delivery platform. Its intrinsic ability to specifically bind the tumor-overexpressed transferrin receptor 1 (TfR1/CD71) and penetrate the blood-brain barrier (BBB) provides a unique solution for the precise delivery of chemotherapeutics, metal ions, gene therapy molecules, and novel therapeutics.

MAIN FINDINGS: Ferritin achieves efficient loading of diverse therapeutics (chemotherapeutic agents, metal ions, siRNA) through pH-mediated reassembly, thermally-gated mechanisms, or high hydrostatic pressure methods. Genetic and chemical engineering enhances its intrinsic TfR1/CD71 targeting affinity, significantly improving penetration specificity toward tumor cells and the blood-brain barrier. Successful delivery of regorafenib and immune checkpoint inhibitors to central nervous system tumors has been demonstrated, while combination therapy with ferroptosis inducers or natural bioactive compounds exhibits synergistic efficacy in breast cancer models. Furthermore, ferritin demonstrates potential for multimodal therapeutic integration with ferroptosis induction, photodynamic therapy, and immune checkpoint blockade strategies.

CONCLUSION

Ferritin nanocarriers exhibit significant advantages for targeted cancer therapy, particularly in blood-brain barrier penetration and precise delivery. Genetic/chemical engineering enhances their efficacy. However, clinical translation faces key challenges: optimizing drug-carrier compatibility, characterizing in vivo pharmacokinetics, and achieving scalable production. Future research priorities include developing smart stimuli-responsive release systems, establishing multimodal therapeutic regimens, and standardizing manufacturing protocols to advance clinical application.