Engineering peptides into antibodies—opportunities and strategies for therapeutic innovation

Peptides and antibodies occupy complementary therapeutic niches. Peptides offer compact size and high-affinity recognition of difficult targets, whereas antibodies provide exquisite specificity, long serum half-life, and effector functions. Here we review strategies that merge these modalities by engineering peptides into immunoglobulins and antibody fragments. We discuss peptide grafting into hypervariable and framework loops, terminal fusion to antibody chains, Fc-peptide fusion proteins, and bioconjugation approaches. Across these formats, we examine examples that illustrate the importance of insertion site, peptide topology, and linker design for folding, activity, and developability. We highlight how antibody fusion and conjugation with natural and engineered peptides can confer novel target binding, conditional activation, altered biodistribution, improved pharmacokinetics, or intracellular delivery, and we discuss how disulfide-rich and macrocyclic peptides have enriched the design space. Finally, we also point out key translational challenges, including manufacturability, stability, heterogeneity, and immunogenicity, and propose that advances in protein design and chemical bioconjugation will enable next-generation therapeutics at the interface of antibodies and peptides.