Currently, bioengineered apoferritin nanocages with flexible protein shells and functionalized modifications have become an attractive approach for efficient anti-tumor therapy. Here, we modified the N-terminus of H-chain subunits in apoferritin with different amounts of lysine via genetic recombination to obtain a poly(L-lysine) modified H-chain apoferritin (nL-HFn) nanocage for siRNA delivery and gene therapy. To achieve excellent cellular affinity and uptake, the nanocarriers were internalized through transferrin receptor-mediated endocytosis, then escaped from the endosome for cytoplasmic transport. Compared with natural apoferritin, the siRNA-loaded genetic recombination NPs modified with lysine exhibit stronger RNA-interference and antitumor efficiency both in vitro and in 4T1 tumor model mice. Therefore, bioengineered apoferritin nanocages modified with lysine might be a promising platform for nucleic acid drug delivery.