Recent Advances in Peptide−Oligonucleotide Conjugates for Enhanced Therapeutic Efficacy

Abstract Oligonucleotide therapeutics have emerged as next-generation therapeutics. However, targeted delivery of oligonucleotides to extrahepatic tissues, such as skeletal and cardiac muscles and the central nervous system, at efficacious yet well-tolerated doses remain a major challenge for their clinical translation. Although antibody−oligonucleotide conjugates are promising for the treatment of genetic disorders, inadequate tissue penetration and immunogenicity have constrained their therapeutic efficacy. By combining the advantages of cell-penetrating peptides (CPPs) or cell-targeting peptides (CTPs) with those of oligonucleotides, peptide−oligonucleotide conjugates (POCs) display enhanced cellular uptake, endosomal escape, and extrahepatic delivery. The therapeutic efficacy of POC was increased through conjugation with CPPs, endosomal-escape peptides (EEPs), fusogenic peptides, nuclear localization signal peptides, or CTPs. In this perspective, innovative molecular designs such as multivalent, cyclic, and chimeric peptides, and combinations of CPPs and EEPs, were explored, highlighting key advancements in POC development and providing insights into future directions for the development of novel POCs.