Advances in Peptide-Based Therapeutics: Formulation Strategies and Targeted Drug Delivery Systems

Abstract

Peptide-based therapeutics have become a flexible type of medicine that combines high target specificity and strong biological activity with good safety profiles. They effectively connect small-molecule drugs and biologics. Since insulin was first used in 1922, more than 100 peptide drugs have been approved around the world, and their use is growing in diabetes, cancer, rare diseases, and autoimmune disorders. However, their clinical use is still limited by rapid enzymatic degradation, short half-life, poor membrane permeability, low oral bioavailability, and formulation instability. This review presents a unified innovation framework that integrates upstream molecular engineering strategies including cyclization, peptide stapling, D- and β-amino acid substitution, PEGylation, and backbone modification with downstream advanced delivery platforms such as nanocarriers, microneedles, self-assembling hydrogels, and stimuli-responsive systems, while also addressing critical translational considerations including scalability, regulatory requirements, and manufacturing consistency. By critically linking structural modifications at the molecular level with formulation performance and clinical translation factors, and by evaluating both approved products and persistent gaps in predictive modelling and patient-centric delivery, this work offers practical insights that go beyond the scope of most existing reviews. The integrated perspective presented here highlights how these combined approaches are shifting peptide therapeutics from conventional injectable formats toward more stable, convenient, and precisely targeted solutions, paving the way for the next generation of patient-friendly peptide medicines.