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

This review presents a three-tiered engineering framework that systematically addresses these barriers. First, we survey chemical and sequence-based stabilization strategies, including lipidation, backbone N-methylation, and cyclization, that convert labile natural peptides into protease-resistant scaffolds. Second, moving beyond generic stabilization, we dissect the rational design of effector-inhibitory peptides, with particular emphasis on disulfide bond topology engineering as a powerful means to lock binding-competent conformations, alongside structure-guided interface optimization. Third, recognizing that purely rational design often fails to correctly fold complex topologies, we discuss complementary structure-constrained screening platforms (phage display, yeast display, and in silico docking) that exploit sequence–conformation coupling to enrich functional structures from vast libraries. Critically, we argue that these molecular-level designs can only achieve in vivo efficacy when co-integrated with delivery systems, including lipidic, polymeric, and viral carriers, which together determine bioavailability, targeting, and controlled release. By weaving these layers into a unified framework, we highlight a paradigm shift from sequential optimization toward context-aware co-design, where peptide rigidity, flexibility, affinity, and carrier compatibility are balanced against specific therapeutic or industrial contexts.