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 emergence of three parts in one system, i.e., electrostatic complexation of peptide with PEG-NAs via nonreducible and reducible agents. 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 spiders.