Cross-linking of protein macromonomers accompanies the assembly of viral particles, which provides the virus with high stability in the host. Following inspiration, caged polyplexes were fabricated via a biomimetic cross-linker. Thiolated polyethylenimine was synthesized and showed sufficient DNA condensation ability. Spherical particles with a diameter of about 150nm were formed at an N/P ratio of 10. Shell-cross-linked polyplexes were then constructed by the oxidation of thiol groups in air. All the results indicate that the cross-linking shell via disulfide bonds could improve the stability of polyplexes in the physiological condition and showed a reversible unpacking property at the intracellular GSH concentration. By selecting the proper preparation conditions, polyplexes caged via a biomimetic cross-linker could efficiently release DNA for transfection.