Integration of organoids in peptide drug discovery: Rise of the high-throughput screening

Organoids are three-dimensional cell aggregates with near-physiologic cell behaviors and can undergo long-term expansion in vitro. They are amenable to high-throughput drug screening processes, which renders them a viable preclinical model for drug development. The procedure of organoid-based high-throughput screening has been extensively employed to discover small-molecule drugs, encompassing the steps of generating organoids, examining efficient drugs in organoid cultures, and data assessment. Compared to small molecules, peptides are more straightforward to synthesize, can be modified chemically, and demonstrate high target specificity and low cytotoxicity. Therefore, they have emerged as promising carriers to deliver drugs to disease-associated targets and could be efficient therapeutic drugs for various diseases. To date, organoids have been used to evaluate the efficacy of certain peptide agents; however, no organoid-based high-throughput screening of peptide drugs has been reported. Given the advantages of peptide drugs, there is an urgent need to establish organoid-based peptide high-throughput screening platforms. In this review, we discuss the typical approach of screening small-molecular drugs with the use of organoid cultures, as well as provide an overview of the studies that have incorporated organoids in peptide research. Drawing on the knowledge from small molecular screens, we explore the difficulties and potential avenues for creating new platforms to identify peptide agents using organoid models.