Therapeutic Peptides as Targeting Vectors and Smart Therapeutics: Emerging Trends and Future Perspectives

Ever since the first monumental discovery in 1921, peptide science has evolved into the field of therapeutic peptides (TPs), whose unique biochemical properties bridge the gaps associated with small molecules and biologics. Despite the fascinating therapeutic potential of TPs, such as lower immunogenicity, targeting specificity, binding affinity, favorable safety profiles, relatively easy synthesis, chemical flexibility, and diversity in physiological functions, the use of TPs in clinical settings is hampered by their shortcomings. Persistent issues such as poor oral bioavailability, susceptibility to enzymatic degradation, and short in vivo half-life limit their clinical application. This review provides a comprehensive overview of the evolving landscape of peptide therapeutics, with emphasis on innovative strategies to overcome the aforementioned challenges. Key advancements include peptide-drug conjugates (PDCs), peptide-nanoparticle conjugates (PNCs), synergistic peptide combinations, stimuli-responsive smart peptide systems, multifunctional peptides, as well as peptide-directed delivery of genetic products such as CRISPR technology and RNA therapeutics. In particular, the review focuses on the latest cutting-edge innovations in TP applications such as cancer theranostics, immunotherapy, gene delivery systems, and precision nanomedicine. Moreover, the integration of artificial intelligence (AI)-driven models in tumor diagnostics, treatment decisionmaking, peptide design, and peptide discovery has served as a pivotal advancement in the utilization of bioinformatic technologies for enhanced diagnostic precision and improved treatment efficiency through machine learning. Highlights of current advances and future directions in this review aim to provide research and translational insights into therapeutic peptide design, delivery, and nextgeneration peptide-based therapeutics.