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Advances in the 3D Culture Systems and Organoids for Disease Modeling and Therapeutics

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 October 2025) | Viewed by 6512

Special Issue Editor

Prof. Dr. Su-Yun Lyu

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Guest Editor
Department of Pharmacy, Sunchon National University, Suncheon 57922, Jeollanam-do, Republic of Korea
Interests: anticancer drug discovery; natural products
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue highlights the recent advances in 3D culture systems and organoids for disease modeling and therapeutic development. These innovative systems provide more physiologically relevant models than traditional 2D cultures, aiding in the breakthroughs in understanding disease processes and creating new therapeutic strategies. We welcome submissions across a broad range of topics, including the use of 3D models and organoids in drug discovery, regenerative medicine, and biomaterials for therapeutic applications. Studies exploring the molecular mechanisms involved in disease progression and treatment responses are also encouraged. Additionally, novel approaches utilizing 3D systems in cancer, immunology, and other fields are welcome. The aim of this Special Issue is to provide a platform for interdisciplinary research that advances personalized medicine and therapeutic innovation.

Prof. Dr. Su-Yun Lyu
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • 3D culture systems
  • organoids
  • disease modeling
  • drug discovery
  • regenerative
  • medicine biomaterials
  • molecular mechanisms
  • cancer
  • immunology
  • personalized medicine

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Published Papers (3 papers)

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Research

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21 pages, 5820 KB  
Article
Transcriptomic Profile of Directed Differentiation of iPSCs into Hepatocyte-like Cells
by Irina Panchuk, Valeriia Kovalskaia, Konstantin Kochergin-Nikitsky, Valentina Yakushina, Natalia Balinova, Oxana Ryzhkova, Alexander Lavrov and Svetlana Smirnikhina
Int. J. Mol. Sci. 2026, 27(2), 633; https://doi.org/10.3390/ijms27020633 - 8 Jan 2026
Viewed by 318
Abstract
The liver is the central organ in metabolism; however, modeling hepatic diseases remains limited by current experimental models. Animal models frequently fail to predict human liver physiology, while primary hepatocytes rapidly dedifferentiate in culture. We performed comprehensive transcriptomic profiling of induced pluripotent stem [...] Read more.
The liver is the central organ in metabolism; however, modeling hepatic diseases remains limited by current experimental models. Animal models frequently fail to predict human liver physiology, while primary hepatocytes rapidly dedifferentiate in culture. We performed comprehensive transcriptomic profiling of induced pluripotent stem cells (iPSCs) differentiation into hepatocyte-like cells (HLCs) under two-dimensional (2D) and three-dimensional (3D) culture conditions. RNA sequencing analysis revealed the sequential activation of lineage-specific markers across major developmental stages: definitive endoderm (FOXA2, SOX17, CXCR4, CER1, GATA4), posterior foregut (PROX1, GATA6), and hepatoblasts (HNF4A, AFP). Comparative analysis demonstrated a markedly enhanced hepatic gene expression of 3D organoids, as demonstrated by a 33-fold increase in HNF4A expression and elevated levels of mature hepatocyte markers, including ALB, SERPINA1, and UGT2B15. However, the 3D cultures retained fetal characteristics (290-fold higher AFP expression) and exhibited significantly impaired metabolic function, with CYP3A4 expression levels reduced by 2000-fold compared to the adult human liver. This partial maturation was further supported by a moderate correlation with adult liver tissue (ρ = 0.57). We demonstrated high reproducibility across five biologically distinct iPSCs lines, including those derived from patients with rare monogenic disorders. The establishment of quantitative benchmarks provides a crucial tool for standardizing in vitro liver models. Furthermore, we delineate the specific limitations of the current model, highlighting the need for further protocol optimization to enhance metabolic maturation and P450 enzyme activity. Functional validation of metabolic activity (CYP enzyme assays, albumin secretion) was not performed; therefore, conclusions regarding hepatocyte functionality are based on transcriptomic evidence. Full article
(This article belongs to the Special Issue Advances in the 3D Culture Systems and Organoids for Disease Modeling and Therapeutics)
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22 pages, 5106 KB  
Article
KCNV2-Deficient Retinal Organoid Model of Cone Dystrophy—In Vitro Screening for AAV Gene Replacement Therapy
by Sophie L. Busson, Arifa Naeem, Silvia Ferrara, Shilpita Sarcar, Toyin Adefila-Ideozu, Sarah Wells, Sophia El Alami, James Boot, Paul E. Sladen, Michel Michaelides, Anastasios Georgiadis and Amelia Lane
Int. J. Mol. Sci. 2026, 27(1), 449; https://doi.org/10.3390/ijms27010449 - 31 Dec 2025
Viewed by 681
Abstract
KCNV2 encodes Kv8.2, an electrically silent voltage-gated potassium channel subunit that is expressed in photoreceptors. Disease-causing variants in KCNV2 cause a monogenic disorder which is classified clinically as cone dystrophy with supernormal rod response (CDSRR). Here, we generated KCNV2-deficient human retinal organoids [...] Read more.
KCNV2 encodes Kv8.2, an electrically silent voltage-gated potassium channel subunit that is expressed in photoreceptors. Disease-causing variants in KCNV2 cause a monogenic disorder which is classified clinically as cone dystrophy with supernormal rod response (CDSRR). Here, we generated KCNV2-deficient human retinal organoids as a tool for gene therapy vector potency assessment. The organoids were derived from two separate sources: by generating IPSCs from patient blood and by gene editing of a control cell line. Eight KCNV2 gene therapy vectors were assessed in retinal organoids; Kv8.2 protein levels and its in situ interactions with potassium channel binding partners were quantitatively assessed. We show significant enhancements in vector potency and specificity by transgene codon optimisation and the use of the photoreceptor-specific rhodopsin kinase (RK) promoter, respectively. Single-cell RNA sequencing was performed in transduced retinal organoids to assess the performance of the AAV vectors at single-cell resolution. KCNV2-deficient photoreceptors had an upregulation in genes associated with apoptosis, oxidative stress, and hypoxia pathways which were partially restored in AAV-KCNV2 transduced photoreceptors. These data show how human retinal organoids can be used to evaluate AAV gene therapy vector potency in vitro in a physiologically relevant model for the selection of lead therapeutic candidates and to help minimise the use of animals in preclinical development. Full article
(This article belongs to the Special Issue Advances in the 3D Culture Systems and Organoids for Disease Modeling and Therapeutics)
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Review

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33 pages, 1777 KB  
Review
Immunomodulatory Natural Products in Cancer Organoid-Immune Co-Cultures: Bridging the Research Gap for Precision Immunotherapy
by Chang-Eui Hong and Su-Yun Lyu
Int. J. Mol. Sci. 2025, 26(15), 7247; https://doi.org/10.3390/ijms26157247 - 26 Jul 2025
Cited by 4 | Viewed by 4883
Abstract
Natural products demonstrate potent immunomodulatory properties through checkpoint modulation, macrophage polarization, and T cell/natural killer (NK) cell activation. While cancer organoid-immune co-culture platforms enable physiologically relevant modeling of tumor–immune interactions, systematic investigation of natural product immunomodulation in these systems remains entirely unexplored. We [...] Read more.
Natural products demonstrate potent immunomodulatory properties through checkpoint modulation, macrophage polarization, and T cell/natural killer (NK) cell activation. While cancer organoid-immune co-culture platforms enable physiologically relevant modeling of tumor–immune interactions, systematic investigation of natural product immunomodulation in these systems remains entirely unexplored. We conducted a comprehensive literature analysis examining natural products tested in cancer organoids, immunomodulatory mechanisms from traditional models, technical advances in organoid-immune co-cultures, and standardization requirements for clinical translation. Our analysis reveals a critical research gap: no published studies have investigated natural product-mediated immunomodulation using organoid-immune co-culture systems. Even though compounds like curcumin, resveratrol, and medicinal mushroom polysaccharides show extensive immunomodulatory effects in two-dimensional (2D) cultures, and organoid technology achieves high clinical correlation for drug response prediction, all existing organoid studies focus exclusively on direct cytotoxicity. Technical challenges include compound stability, limited matrix penetration requiring substantially higher concentrations than 2D cultures, and maintaining functional immune populations in three-dimensional (3D) systems. The convergence of validated organoid-immune co-culture platforms, Food and Drug Administration (FDA) regulatory support through the Modernization Act 2.0, and extensive natural product knowledge creates unprecedented opportunities. Priority research directions include systematic screening of immunomodulatory natural products in organoid-immune co-cultures, development of 3D-optimized delivery systems, and clinical validation trials. Success requires moving beyond cytotoxicity-focused studies to investigate immunomodulatory mechanisms in physiologically relevant 3D systems, potentially unlocking new precision cancer immunotherapy approaches. Full article
(This article belongs to the Special Issue Advances in the 3D Culture Systems and Organoids for Disease Modeling and Therapeutics)
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