Functional Peptide-Based Biomaterials for Pharmaceutical Application: Sequences, Mechanisms, and Optimization Strategies

Peptide-based biomaterials have emerged as versatile tools for pharmaceutical Drug Delivery due to their biocompatibility and tunable sequences, yet a comprehensive overview of their categories, mechanisms, and optimization strategies remains lacking to guide clinical translation. This review systematically collates advances in peptide-based biomaterials, covering peptide excipients (cell penetrating Peptides, tight junction modulating Peptides, and peptide Surfactants/stabilizers), Self-assembling Peptides (peptide-based nanospheres, cyclic peptide nanotubes, nanovesicles and micelles, peptide-based hydrogels and depots), and Peptide Linkers (for antibody drug-conjugates, peptide drug-conjugates, and prodrugs). We also dissect sequence-based optimization strategies, including rational design and biophysical optimization (cyclization, stapling, D-amino acid incorporation), functional motif integration, and combinatorial discovery with AI assistance, with examples spanning marketed drugs and research-stage candidates. The review reveals that Cell-penetrating Peptides enable efficient intracellular payload delivery via direct penetration or endocytosis; Self-assembling Peptides form diverse nanostructures for controlled release; and Peptide Linkers achieve site-specific drug release by responding to tumor-associated Enzymes or pH cues, while sequence optimization enhances stability and targeting. Peptide-based biomaterials offer precise, biocompatible and tunable solutions for Drug Delivery, future advancements relying on AI-driven design and multi-functional modification will accelerate their transition from basic research to clinical application.