Recent Advances in the Synthesis of Therapeutic Peptides and Oligonucleotides

Abstract Peptide and oligonucleotide synthesis is an emerging indispensable molecular platform in modern medicine due to their inherent property of exceptional target specificity and broad therapeutic potential. However, their synthetic complexity, inefficiency in production, and issues related to sequence length and structural diversity have restricted their large-scale manufacture. This review presents a broad survey of recent developments in synthetic methodologies that have revolutionized the synthesis of these biomacromolecules, with special emphasis on process-oriented innovations that bridge laboratory synthesis and industrial manufacture. This review discusses the recent development of solid-phase methodologies, improvements in ligation chemistry, orthogonal protecting-group strategies, and chemo-selective conjugation methods that enable the efficient assembly of structurally complex peptide and oligonucleotide architectures, along with emerging technologies, including continuous-flow processing, microwave-assisted synthesis, and atom-economical reaction platforms, which are highlighted for their ability to improve reaction kinetics, reduce solvent consumption, and enhance reproducibility. Furthermore, the growing integration of enzymatic and chemoenzymatic methodologies, including engineered polymerases and template-independent nucleic acid synthesis systems, is redefining the preparation of next-generation oligonucleotides. Particular attention is given to sustainability-driven synthetic innovations that address longstanding limitations related to scalability, purification, stereochemical control, and environmental impact. By comparing the strengths and limitations of conventional synthetic platforms, this review establishes a unified perspective on the evolving manufacturing landscape for peptide and oligonucleotide production, as well as the therapeutic applications of versatile peptide and oligonucleotide substrates. Collectively, these advances provide a foundation for the accelerated development of increasingly sophisticated biomolecular constructs and offer practical insights for translating synthetic innovations into clinically and industrially relevant applications.