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Oral Gene-Editing Nanoparticle Systems Boosting Immunotherapy in Colorectal Cancer: Recent Results


Introduction


Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with limited therapeutic success in advanced and immunotherapy-resistant disease. While immune checkpoint blockade and chemo-immunotherapy have improved outcomes in select patient subsets, most colorectal tumors, particularly microsatellite-stable (MSS) CRC, exhibit intrinsic resistance driven by chemoresistance and an immunosuppressive tumor microenvironment.


Oral cancer theraputics

Recent breakthroughs in oral gene-editing nanoparticle systems offer a promising solution. By enabling the non-invasive delivery of CRISPR–Cas9 payloads directly to colorectal tumors, these systems have demonstrated the ability to reprogram tumor metabolism, overcome chemoresistance, and synergistically enhance the efficacy of immunotherapy.


Key Concepts of Oral Gene-Editing


  • Gene Editing (CRISPR–Cas9):A programmable genome-editing technology that enables precise knockout or modification of disease-driving genes within cells.

  • Oral Nanoparticle Delivery:A drug delivery strategy that allows therapeutic cargos to survive gastric digestion, penetrate intestinal mucus, traverse epithelial barriers, and accumulate in target tissues following oral administration.

  • Tumor Microenvironment (TME):The complex ecosystem of tumor cells, immune cells, stromal components, and metabolic factors that collectively regulate cancer progression and therapy response.

  • Chemo-Immunotherapy Synergy:A therapeutic strategy combining chemotherapy-induced immunogenic cell death with immune checkpoint blockade to amplify anti-tumor immune responses.


Importance of the Topic


Oral gene-editing nanoparticle platforms address several longstanding barriers in cancer nanomedicine:


  1. Patient compliance: Oral administration avoids repeated intravenous dosing.

  2. Localized gene editing: Limits systemic toxicity and off-target immune activation.

  3. Immunotherapy sensitization: Converts “cold” CRC tumors into immunologically active lesions.


Given that CRC originates in the gastrointestinal tract, oral delivery represents a biologically intuitive and clinically translatable route for gene-based immunomodulation.


Current Research and Recent Results

Oral CRISPR Nanoparticles Targeting Chemoresistance Genes


A pivotal 2025 Nature Nanotechnology study reported the development of an orally administered CRISPR–Cas9 nanoparticle system designed to disrupt the mitochondrial chaperone gene TRAP1, a key regulator of chemoresistance and immune suppression in CRC.


Key findings include:


  • Efficient penetration of intestinal mucus and epithelial transcytosis

  • Preferential accumulation in colorectal tumor tissues

  • CRISPR-mediated knockout of TRAP1, inducing mitochondrial permeability transition

  • Enhanced chemotherapy-induced tumor necrosis

  • Increased infiltration of CD8⁺ cytotoxic T cells and reduced immunosuppressive cells


Importantly, oral CRISPR treatment significantly enhanced the efficacy of immune checkpoint blockade, even in chemoresistant and spontaneous CRC models.


Broader Nanoparticle–Gene Editing Landscape


Complementary studies demonstrate that polymeric, lipid-based, and hybrid nanoparticles can deliver gene-editing or gene-silencing cargos to modulate immune pathways and tumor metabolism, thereby reinforcing the generalizability of this approach across gastrointestinal cancers.


Current Challenges


Despite encouraging results, several hurdles remain before clinical translation:


  • Long-term safety of oral CRISPR delivery

  • Precise control of gene-editing specificity in intestinal tissues

  • Manufacturing scalability and regulatory oversight

  • Inter-patient variability in gut physiology and microbiota


Addressing these challenges will require coordinated advances in materials science, gene-editing biology, and clinical trial design.


Summary


Recent advances in oral gene-editing nanoparticle systems represent a transformative step in colorectal cancer therapy. By combining CRISPR-mediated gene disruption with chemo-immunotherapy, these platforms overcome chemoresistance, reprogram the tumor microenvironment, and unlock robust anti-tumor immune responses. While still in the preclinical stage, the strategy holds strong promise for expanding immunotherapy benefits to a broader CRC patient population.


Oral gene editing; CRISPR–Cas9 nanoparticles; colorectal cancer; immunotherapy enhancement; chemo-immunotherapy synergy; tumor microenvironment; nanomedicine

References


  • Zhao, K., Yan, Y., Jin, X.-K., Pan, T., Zhang, S.-M., Yang, C.-H., Rao, Z.-Y., & Zhang, X.-Z. (2025). An orally administered gene editing nanoparticle boosts chemo-immunotherapy in colorectal cancer. Nature Nanotechnology, 20, 935–946. https://doi.org/10.1038/s41565-025-01904-5

  • Wang, X., Yin, X., Li, Y., Zhang, S., Hu, M., Wei, M., & Li, Z. (2024). Novel insight and perspectives of nanoparticle-mediated gene delivery and immune-modulating therapies for pancreatic cancer. Journal of Nanobiotechnology, 22, 771. https://doi.org/10.1186/s12951-024-02975-7

  • Lin, S., Han, S., Wang, X., Wang, X., Shi, X., He, Z., Sun, M., & Sun, J. (2024). Oral micro-to-nano genome-editing system enabling targeted delivery and conditional activation of CRISPR-Cas9 for gene therapy. ACS Nano, 18, 25657–25670. https://doi.org/10.1021/acsnano.4c07750


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Disclaimer

This article is intended solely for educational and informational purposes. It does not constitute medical advice or clinical recommendations. All interpretations are based on peer-reviewed preclinical research, and clinical applicability remains under investigation.

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