The main obstacle in siRNA therapy is RNA delivering to the cytoplasm where it can guide sequence-specific mRNA degradation. Attempts to develop effective nonviral vectors for in vivo delivery of nucleic acids through a systemic route are hampered by difficulties of combining of high extracellular stability with ready availability of the nucleic acids following entry into cells. Extracellular stability is essential as the delivery system should be capable of withstanding the aggressive biological environment en-route to the target site, while availability of the nucleic acids is to permit efficient therapeutic effects within the cells. Other challenges with non-viral gene delivery include limitation in target-cell specificity. Here we demonstrate that the caging of siRNA-PPI nanoparticles with a dithiol containing crosslinkers provides lateral stabilization, preventing unfavorable dissociation of the nanopartices before entering the cytoplasm of target cells through the interaction with negatively charged biomacromolecules in the entity. Further PEGylation of the caged nanoparicles stabilize them against aggregation induced by salts and proteins existed in the serum. Due to the reductive environment in the cytoplasm, the disulfide bonds could be reduced, the lateral crosslinks are removed and the siRNA is released for expression. Furthermore, PEG coating can effectively eliminate nonspecific delivery, increasing targeting delivery efficiency after a specific targeting groups attached to its distal ends.