Patient-Derived Organoids as a Model to Understand Tumor Microenvironment-Driven Nano-Bio Interactions - A Framework Towards Improved Nanomedicine Translation
- 1University of Arizona
Abstract
Nanomedicines that perform well in conventional cell cultures often fail to translate into patients, in part due to the inability to reproduce the protein corona, and hence the biological identity, that nanoparticles acquire within the tumor microenvironment (TME). Here, we establish patient-derived colonic organoids (PDCOs) as a platform for profiling nano-bio interactions under physiologically tumor-relevant conditions using graphene quantum dots (GQD) and Silicon Quantum Dots (SiQD) as material-distinct probes. By combining spectral flow cytometry, confocal imaging, dynamic light scattering, and multi-spectral dimension-reduction analysis of single-cell uptake, we resolve how nanoparticle identity, uptake, and intracellular fate diverge between conventional culture and patient tissue. Conventional two-dimensional culture overestimated internalization by two-fold relative to ex vivo PDCOs, while TME-specific proteins directed nanoparticles to distinct organoid subpopulations. Exploiting this, we engineer the protein corona with tumor-specific proteins to redirect SiQDs to chemoresistant cells, from 3.8% to 70%, an 18-fold increase in targeted delivery to the cells that drive therapy resistance. Internalization was also model-dependent. PDCOs and fibroblasts favored clathrin/dynamin (DNM1)-mediated endocytosis into lysosomes, whereas cancer cells favored caveolae (CAV1)-mediated entry that bypasses lysosomal degradation. This distinction determines whether a nanocarrier is degraded or delivered intact. Collectively, these findings turn the protein corona into a programmable design tool and establish PDCOs as a next-generation platform for precision nano-oncology.
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BibTeX
@misc{resmi2026patientderived,
title = {{Patient-Derived Organoids as a Model to Understand Tumor Microenvironment-Driven Nano-Bio Interactions - A Framework Towards Improved Nanomedicine Translation}},
author = {M. P. Resmi and J. Chakrabarti and K. Pond and S. Ganesh},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.749195},
url = {https://www.biorxiv.org/content/10.64898/2026.09.03.749195v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Patient-Derived Organoids as a Model to Understand Tumor Microenvironment-Driven Nano-Bio Interactions - A Framework Towards Improved Nanomedicine Translation
AU - M. P. Resmi
AU - J. Chakrabarti
AU - K. Pond
AU - S. Ganesh
PY - 2026
DA - 2026/09/03
PB - bioRxiv
DO - 10.64898/2026.09.03.749195
UR - https://www.biorxiv.org/content/10.64898/2026.09.03.749195v1
AB - Nanomedicines that perform well in conventional cell cultures often fail to translate into patients, in part due to the inability to reproduce the protein corona, and hence the biological identity, that nanoparticles acquire within the tumor microenvironment (TME). Here, we establish patient-derived colonic organoids (PDCOs) as a platform for profiling nano-bio interactions under physiologically tumor-relevant conditions using graphene quantum dots (GQD) and Silicon Quantum Dots (SiQD) as material-distinct probes. By combining spectral flow cytometry, confocal imaging, dynamic light scattering, and multi-spectral dimension-reduction analysis of single-cell uptake, we resolve how nanoparticle identity, uptake, and intracellular fate diverge between conventional culture and patient tissue. Conventional two-dimensional culture overestimated internalization by two-fold relative to ex vivo PDCOs, while TME-specific proteins directed nanoparticles to distinct organoid subpopulations. Exploiting this, we engineer the protein corona with tumor-specific proteins to redirect SiQDs to chemoresistant cells, from 3.8% to 70%, an 18-fold increase in targeted delivery to the cells that drive therapy resistance. Internalization was also model-dependent. PDCOs and fibroblasts favored clathrin/dynamin (DNM1)-mediated endocytosis into lysosomes, whereas cancer cells favored caveolae (CAV1)-mediated entry that bypasses lysosomal degradation. This distinction determines whether a nanocarrier is degraded or delivered intact. Collectively, these findings turn the protein corona into a programmable design tool and establish PDCOs as a next-generation platform for precision nano-oncology.
ER -