Review Integrates Advances in Peptide Synthesis, Engineering, and Delivery to Chart Future Biologic Therapeutics

Peptide therapeutics offer a unique blend of high target specificity and potent bioactivity, positioning them between small-molecule drugs and large biologics. Despite these advantages, their broader clinical translation is hindered by inherent limitations such as poor metabolic stability, rapid renal clearance, and limited membrane permeability. This review systematically integrates advances in peptide science, from natural discovery to synthetic methodologies and structural engineering, to identify critical research gaps that impede clinical adoption and the development of next-generation therapies.

This systematic review integrated advances across several key areas of peptide science. It covered natural peptide discovery from diverse sources (plants, animals, microbes, marine, venoms), synthetic methodologies including solid-phase peptide synthesis (SPPS) and green chemistry, and in silico approaches like AI-driven sequence design. The authors also critically evaluated structural modifications such as cyclization, PEGylation, and lipidation, alongside nanoformulation strategies like self-assembling peptides and cell-penetrating systems, to assess their impact on pharmacokinetic and pharmacodynamic properties.

The review highlighted diverse natural sources of bioactive peptides, including plant-derived lunasin, animal-derived Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), microbial nisin and cyclosporine, marine dolastatins, and venom-derived chlorotoxin and ω-conotoxin MVIIA (ziconotide). Significant advances in synthetic methodologies were identified, such as solid-phase peptide synthesis (SPPS), green chemistry, and catalytic strategies, complemented by emerging in silico approaches like AI-driven sequence design. Structural modifications, including cyclization, hydrocarbon stapling, PEGylation, and lipidation, were shown to enhance pharmacokinetic and pharmacodynamic properties. Furthermore, nanoformulation strategies, such as self-assembling peptides and cell-penetrating systems, were examined for their potential to overcome biological barriers. > Importantly, the review identified key unresolved challenges: a lack of predictive models for peptide delivery systems, safety concerns associated with long-term modifications, and limited in vivo validation of naturally derived peptides.