Abstract C127: Modulating the tumor niche-specific protein corona of nanomedicines for the precision targeting of chemoresistant cells using patient-derived organoids

Abstract Minimal residual disease developing after chemotherapy due to resistance has compromised the disease-free survival of cancer patients. A combination of chemotherapy with existing approaches, such as targeted therapy and immunotherapy, has been studied. However, the resistant population often persists. This highlights the need for a next-generation approach to target the residual cell population. Nano-assisted cancer therapy offers a promising method to target these residual cancer cells. However, only a limited number of FDA-approved nanoparticles are available. One primary reason limiting the effectiveness of nanoparticles in clinical trials is the unrestrained formation of a biomolecular corona, comprising mainly proteins. This corona forms when proteins adsorb onto the nanoparticle surface upon exposure to a biological environment. The protein corona plays a crucial role in determining the internalization and localization of nanoparticles, which can cause off-target accumulation. Studies on protein corona have primarily focused on abundant proteins, such as albumin and transferrin, which promote uptake in most cell types, including normal cells. Additionally, chemo-resistant cell populations reside in specific tumor microenvironment niches enriched with low-abundance, distinct proteins that remain largely underexplored. These niche-specific proteins might enhance the selective accumulation of nanoparticles in chemoresistant cells. This research aims to identify and engineer the protein corona to facilitate the entry of nanoparticles into residual cells that exhibit chemoresistance. Methods: Protein corona formation in growth media was optimized, and proteins were isolated from the media by centrifugation. Raman spectroscopy was employed to confirm the formation of a protein corona. Immunofluorescent staining was performed on patient-derived colorectal tumor organoids to analyze uptake. The engineered protein corona was studied to evaluate nanoparticle uptake in chemo-resistant cell populations within colorectal tumor organoids using BD FACS Canto flow cytometry. Results: Protein corona formation is dynamic, and Raman spectroscopy confirmed the presence of proteins by identifying characteristic protein-specific amide bonds in the spectra. WNT and EGF, which are enriched in chemoresistant niches, contribute to the accumulation of nanoparticles in resistant cell populations. Engineering nanoparticles with WNT and EGF enhanced their specific accumulation in the chemoresistant cells within colorectal tumor organoids. Conclusion: Tuning nanoparticles with chemo-resistant niche cues, such as EGF and WNT proteins, enables the development of an innovative delivery platform that targets nanoparticles specifically to chemo-resistant populations, paving the way for next-generation precision nano oncology. Citation Format: Meenu Priya Resmi, Jayati Chakrabarti, Kelvin Pond, Swarna Ganesh. Modulating the tumor niche-specific protein corona of nanomedicines for the precision targeting of chemoresistant cells using patient-derived organoids [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C127.