Biosensors and Nanotheranostics
Bionanotechnology, Drug Delivery, Therapeutics | online ISSN 3064-7789
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Volume 5 Number 1 2026
REVIEWS (Open Access)
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
Abstract
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
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