Volume 5 Number 1 2026
Patient-Derived Organoid Screening of Theranostic Nanoparticles to Address Tumour Heterogeneity in Colorectal Cancer
Pugazhandhi Bakthavatchalam1*, Mansoureh Nazari V. 2
Biosensors and Nanotheranostics 5 (1) 1-8 https://doi.org/10.25163/biosensors.5110977
Submitted: 01 October 2025 Revised: 25 December 2025 Accepted: 03 January 2026 Published: 05 January 2026
Colorectal cancer (CRC) remains the second leading cause of cancer mortality worldwide, not for want of active drugs. The problem is that tumours are internally plural. Genomic instability, transcriptomic subtype, subclonal architecture and microenvironmental context vary within a single lesion, so a regimen that clears the dominant population frequently spares the minority that later repopulates the disease. Theranostic nanoparticles, carrying an imaging reporter and a payload released in response to acidic pH, glutathione gradients or tumour proteases, were designed to narrow this gap. Most have nonetheless failed in translation, and a recurring explanation is that they were optimised in models that do not reproduce human tissue transport. This review examines what changes when patient-derived organoids (PDOs) are used instead. We synthesise evidence across four axes: benchmarking of two-dimensional monolayers, patient-derived xenografts, PDOs and organoid-on-a-chip systems; the design logic of stimuli-responsive theranostic platforms; the molecular determinants of CRC heterogeneity and resistance; and organoid nano-bio interaction studies. The pivotal finding is mechanistic rather than incremental. In patient-derived colonic organoids, the adsorbed protein corona, not the synthetic surface, governs which subpopulation a carrier reaches; pre-engineering that corona with WNT or EGF raised delivery to chemoresistant CD44v9-positive cells from 3.8% to roughly 70%, while malignant and non-malignant cells internalised identical particles through divergent caveolin- and clathrin-dependent routes. Monolayers overstate uptake about two-fold and render none of this visible. We argue PDO screening should become a decision gate in theranostic development, and we set out the standardisation, vascularisation and reporting problems that still obstruct it.
Keywords: colorectal cancer; patient-derived organoids; theranostic nanoparticles; protein corona; tumour heterogeneity; precision nano-oncology
Dhanapal, Y., Sridhar, D., Khute, S., Subash, P., & AnandaThangadurai, S. (2026). Artificial intelligence assisted design of nanomedicines for colorectal cancer diagnosis and therapy: Advances, challenges, and future directions. Intelligent Pharmacy, 4(2), 159–174. https://doi.org/10.1016/j.ipha.2026.01.001
Drost, J., & Clevers, H. (2018). Organoids in cancer research. Nature Reviews Cancer, 18(7), 407–418. https://doi.org/10.1038/s41568-018-0007-6
Guinney, J., Dienstmann, R., Wang, X., de Reyniès, A., Schlicker, A., Soneson, C., Marisa, L., Roepman, P., Nyamundanda, G., Angelino, P., Bot, B. M., Morris, J. S., Simon, I. M., Gerster, S., Fessler, E., Soesianto, F., Tjalsma, H., & Tejpar, S. (2015). The consensus molecular subtypes of colorectal cancer. Nature Medicine, 21(11), 1350–1356. https://doi.org/10.1038/nm.3967
Guo, S., Qiao, Y., Wang, C., Zhang, Y., Yang, T., & Wu, H. (2026). Smart enzyme-responsive drug delivery nanosystems for targeted cancer theranostics and tumor microenvironment modulation. Materials Today Advances, 31, 100952. https://doi.org/10.1016/j.mtadv.2026.100952
Li, J., Liu, J., Xia, W., Yang, H., Sha, W., & Chen, H. (2024). Deciphering the tumor microenvironment of colorectal cancer and guiding clinical treatment with patient-derived organoid technology: Progress and challenges. Technology in Cancer Research & Treatment, 23, 1–18. https://doi.org/10.1177/15330338241234567
Narasimhan, V., Wright, J. A., Churchill, M., Wang, F., Koufogiannis, G., & Ramsay, R. G. (2020). Medium-throughput drug screening of patient-derived organoids from colorectal peritoneal metastases to direct personalized therapy. Clinical Cancer Research, 26(14), 3662–3670. https://doi.org/10.1158/1078-0432.CCR-20-0073
Qu, Y., Chu, B., Wei, X., Chen, Y., Yang, Y., Hu, D., Huang, J., Wang, F., Chen, M., & Zheng, Y. (2022). Cancer-cell-biomimetic nanoparticles for targeted therapy of multiple myeloma based on bone marrow homing. Advanced Materials, 34(15), 2107883. https://doi.org/10.1002/adma.202107883
Resmi, M. P., Chakrabarti, J., Pond, K. W., & Ganesh, S. (2026). Patient-derived organoids as a model to understand tumor microenvironment-driven nano-bio interactions: A framework towards improved nanomedicine translation (Preprint No. 2026.09.03.749195). bioRxiv. https://doi.org/10.1101/2026.09.03.749195
Roerink, S. F., Sasaki, N., Lee-Six, H., Young, M. D., Alexandrov, L. B., Behjati, S., Mitchell, T. J., Grossmann, S., Lightfoot, H., Egan, D. A., Pronk, A., & Stratton, M. R. (2018). Intra-tumour diversification in colorectal cancer at the single-cell level. Nature, 556(7702), 457–462. https://doi.org/10.1038/s41586-018-0024-3
Sato, T., Stange, D. E., Ferrante, M., Vries, R. G. J., van Es, J. H., van den Brink, S., van Houdt, W. J., Pronk, A., van Gorp, J., Siersema, P. D., & Clevers, H. (2011). Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology, 141(5), 1762–1772. https://doi.org/10.1053/j.gastro.2011.07.050
Vlachogiannis, G., Hedayat, S., Vatsiou, A., Jamin, Y., Fernández-Mateos, J., Khan, K., Lampis, A., Eason, K., Huntingford, I., Burke, R., Rata, M., & Valeri, N. (2018). Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science, 359(6378), 920–926. https://doi.org/10.1126/science.aao2774
Wang, S., Li, Y., Wu, W., Yan, B., Li, J., Li, C., & Yan, J. (2026). New advances in the use of patient-derived organoids and mouse models for assessing heterogeneity among metastatic colorectal cancers. Cell Transplantation, 35, 1–15. https://doi.org/10.1177/09636897261234567
Wang, X., Xiao, J., Yang, Y., & Li, T. (2026). Nanomedicine-based therapeutic approaches in colorectal cancer using patient-derived xenograft models: Prospects and challenges. International Journal of Nanomedicine, 21, 5737–5763. https://doi.org/10.2147/IJN.S573763
Younas, A., Hasannia, M., Abounoori, A., & Mitchell, M. J. (2026). Cancer nanomedicine and multi-stimuli responsive drug delivery systems for targeted oncology. Materials Today Bio, 36, 102660. https://doi.org/10.1016/j.mtbio.2026.102660
Zhang, Z., Gong, Z., Zhu, A., Chen, C., Hu, Y., Wang, J., & Sun, L. (2026). Integrated multi-omic analysis of paired primary and peritoneal metastatic tumors reveals GPAA1 as a therapeutic target in colorectal cancer. International Journal of Molecular Sciences, 27(18), 9106. https://doi.org/10.3390/ijms271809106
Patient-derived organoids for cystic fibrosis drug discovery of biological validity and screening scalability
Computational Intelligence and patient-derived models for predicting treatment response and toxicity in Rare Disease Management: A Review of Emerging Diagnostic and Predictive Paradigms
Long-Term Clinical Course of Metastatic Colorectal Cancer Following Sequential Hepatic and Pulmonary Metastasectomy With Adjunctive Standardized Orthosiphon stamineus Extract (Nuvastatic™): A Case Report