A natural drug entry channel in the ferritin nanocage

•A thermal-responsive drug entry channel in the H-ferritin nanocage is identified based on crystal structure and protein mutation analyses.•A mild channel-based drug loading strategy that avoids the denaturization of HFn protein cage with denaturing agents is developed.•Loading doxorubicin into HFn nanocage by the channel-based method significantly increases drug loading capacity and HFn recovery rate.•Channel-based strategy produced HFn-Dox exhibits increased stability, better biosafety, and enhanced antitumor action than other methods.•The drug entry channel is also accessible by multiple small molecule anticancer drugs.