<p indent=0mm>Ferritin, owing to its unique nanocage architecture, self-assembling ability, inherent tumor-targeting, excellent biocompatibility and capability to be produced on a large scale, has emerged as a promising nano-drug carrier for clinical translation. Currently, loading of anti-tumor drug, especially doxorubicin (Dox), in ferritin has been widely investigated via either passive encapsulation or active internalization. Among these methods, strategies that pre-complex metal ions with Dox to form “metal-Dox” complexes that promote entry of Dox into the cavity of ferritin actively enable higher loading capacity and enhanced killing effect. However, these ways currently used still suffer from low recovery rate and impaired integrity. In order to overcome these shortcomings, we here report a new loading strategy, a temperature-related and iron ion-depended method, in which we utilized human heavy chain ferritin (human HFn) and successfully constructed the HFn(Fe-Dox) drug delivery system (HFeD), which achieved a high loading capacity (80–100 Dox per HFn), high encapsulation rate (50%–63%) and considerable recovery rate of HFn (80%–90%). Meanwhile, the strategy reported here preserves the structural integrity, tumor-targeting and controlled drug release of HFn, and thus HFeD is able to specifically target and kill tumor cells, which will inform the druggability of HFeD and application of ferritin-based nano-drug carriers.