Peptide spiders are emerging as novel therapeutic interventions for nucleic acid delivery.

The FDA has approved many nucleic acid (NA)-based products. The presence of charges and biological barriers however affect stability and restrict widespread use. The electrostatic complexation of peptide with polyethylene glycol-nucleic acids (PEG-NAs) via nonreducible and reducible agents lead to three parts at one platform.. The reducible linkage made detachment of siRNA from PEG easy compared with a nonreducible linkage. A peptide spider produces a small hydrodynamic particle size, which can improve drug release and pharmacokinetics. Several examples of peptide spiders that enhance stability, protection and transfection efficiency are discussed. Moreover, this review also covers the challenges, future perspectives and unmet needs of peptide-PEG-NAs conjugates for NAs delivery.