Introduction
Peptides consist of 5-50 amino acids and have a molecular weight between small molecules (500 Da) and antibodies (5000 Da)1, 2. Unlike small molecules, they are also not susceptible to degradation in the human body, and thus display longer tumor retention. Moreover, peptides can be rationally designed based on the sequence of protein targets or interaction binding sites, affording them higher specificity and selectivity than small molecules. Compared to antibodies, the smaller peptides have a shorter clearance time from healthy organs and can be easily synthesized or chemically modified 3-6. Therefore, peptides are emerging as efficient treatment modalities for various diseases. They can be used as carriers for delivery of drugs to disease-associated targets7. For example, peptide-conjugated radionuclides are an efficient approach to delivering local radiation to cancer targets and killing tumor cells1, 8, 9. Cell-penetrating peptides are potential carriers to send drugs across the blood-brain barrier into the brain. Many peptides also show remarkable therapeutic efficacy, which could also serve as a treatment modality10-12. Multiple peptide-based drugs have been approved for clinical practice, highlighting the need for further studies to develop more efficient peptide drugs 6.
However, one of the largest gaps between basic research and clinical application for screening peptide drugs as potential treatments derives from the differences between existing preclinical models and human13. The animal models and two-dimensional (2D) cell lines cannot fully preserve characteristics of in vivo human cells, contributing to the high failure rate of tested drugs in phase I–III clinical trials, resulting in a significant waste of medical resources14-16. The emergence of organoids provides new insights into establishing a novel model system. Organoids are three-dimensional (3D) multicellular constructs primarily generated from pluripotent stem cells (PSCs) and adult stem cells (ASCs) through self-organization and self-renewal13. They can recapitulate the structural and functional features of their in vivo counterparts17-19. Compared to time-consuming animal models, organoids are easy to establish and manipulate20-29. Importantly, they can be used to study the mechanism of human diseases that are difficult to model in animals25, 30, 31. Although human cells can be maintained under two-dimensional conditions, they almost lose the features of native organs due to the lack of a similar microenvironment24, 32, 33. The three-dimensional cultured organoids exhibit near-physiologic cellular composition and behaviors, and maintain genome stability even after long-term expansion18. These advantages make organoids suitable preclinical models for high-throughput drug screening, which help to exclude a series of resistant drugs in the human body, which thus provides an effective approach to develop new drugs (Figure 1)34-37.
A wide range of studies have focused on evaluating the feasibility and utility of organoids in small molecular drug screens, from investigating drug response to establishing organoid-based high-throughput screening platforms13, 38, 39. Although there are several applications of organoids in studying peptide-based drugs, a high-throughput organoid-based platform for screening peptides has not been reported. Given the advantages of peptides, we believe the organoid models will facilitate the development and clinical application of peptide-conjugated drugs and therapeutic peptides. This review discusses the advantages of organoids in peptide drug screens and how we learn from organoid-based small molecular drug screening platforms based on the feature of peptides. In the first part, the typical studies involving small molecular drug application in organoid models are introduced, and an overview of the methodology and theory of these studies are provided. The second part discusses the recent attempts to introduce peptide drugs in organoid models and presents the perspective and challenges of organoid-based high throughput peptide screening platforms.