Human ferritins are emerging platforms for nontoxic protein-based drug delivery, owing to their intrinsic or acquirable targeting abilities to cancer cells and hollow cage structures for drug loading. However, reliable strategies for high-level drug encapsulation within ferritin cavities and prompt cellular drug release are still lacking. Ferritin nano-cages were developed with partially opened hydrophobic channels, which provide stable routes for spontaneous and highly accumulated loading of FeII-conjugated drugs as well as pH-responsive rapid drug release at endoplasmic pH. Multiple cancer-related compounds, such as doxorubicin, curcumin, and quercetin, were actively and heavily loaded onto the prepared nicked ferritin. Drugs on these minimally modified ferritins were effectively delivered inside cancer cells with high toxicity.