Chemical Strategies for Ferritin Nanocage Functionalization: A Viewpoint.

Abstract

As a highly symmetrical and endogenous protein-based drug delivery system, ferritin nanocage has garnered tremendous attention in nanomedicine due to its exceptional biocompatibility, dynamic self-assembly behavior, and intrinsic receptor-mediated targeting capabilities. With the rapid evolution of bioconjugation chemistry and protein engineering, the functional manipulation of ferritin has transitioned from passive physical encapsulation to precise, site-specific engineering of ferritin architectures. This Viewpoint systematically highlights the multidimensional bioconjugation strategies of ferritin and its relatives. We specifically focus on the biochemical principles driving genetic fusion engineering, classic covalent chemical conjugation, modular bioorthogonal assembly, and the in situ construction of catalytic centers within the inner cavity. These chemistries are not merely incremental refinements. They unlock entirely new therapeutic and diagnostic capabilities, including single-dose tumor-lethal chemotherapy, high-sensitivity multimodal/nuclear imaging, targeted protein degradation, ultrapure nanovaccines, and inflammation intervention. This Viewpoint aims to provide a chemically grounded and forward-looking roadmap for the next generation of ferritin engineering.