Rational Design and Delivery of Engineered Peptides: Toward a Unified Framework for Structure, Screening, and Application

Abstract

Simple Summary Engineered peptides represent a promising class of functional molecules positioned between small chemicals and large protein biologics, offering unique advantages in therapeutic, agricultural, and materials applications. However, their practical use is severely constrained by inherent instability, rapid enzymatic degradation, and poor bioavailability. This review provides a systematic overview of current engineering strategies designed to overcome these limitations, organized around a three-tiered framework: chemical modifications that stabilize peptide backbones, structure-guided rational design that locks peptides into bioactive conformations, and high-throughput screening platforms that identify functional variants from vast sequence libraries. We further emphasize that molecular-level improvements alone are insufficient; effective in vivo application requires integration with delivery systems, including liposomal, polymeric, and viral carriers, that collectively govern bioavailability, targeting specificity, and controlled release. By weaving these interconnected layers into a unified perspective, this review highlights a paradigm shift from sequential optimization toward context-aware co-design, in which peptide rigidity, flexibility, affinity, and carrier compatibility are balanced against specific application contexts. The convergence of rational design, artificial intelligence-assisted prediction, and system-level formulation holds considerable promise for establishing engineered peptides as a versatile and transferable molecular toolkit, provided that challenges in scalability, predictability for non-canonical sequences, and regulatory adaptation are addressed in parallel.