Delivery of Engineered Primary Tumor-Derived Exosomes Effectively Suppressed the Colorectal Cancer Chemoresistance and Liver Metastasis

Abstract

Liver metastasis is one of the major causes of colorectal cancer (CRC)-related morbidity and mortality. Delivering small interfering RNAs (siRNAs) or noncoding RNAs has been reported as a promising method to target liver metastasis and chemoresistance in CRC. Here, we report a noncoding RNA delivery system using exosomes derived from primary patient cells. Coiled-coil domain-containing protein 80 (CCDC80) was strongly associated with CRC liver metastasis and chemoresistance, a finding validated by bioinformatic analysis and clinical specimens. Silencing CCDC80 significantly increased sensitivity to chemotherapy agents in OXA-resistant cell lines and a mouse model. The primary cell-derived exosome delivery system was designed to simultaneously deliver siRNAs targeting CCDC80 and increase chemotherapy sensitivity in the distant CRC liver metastasis mouse models and patientderived xenograft mouse models. We further validated the antitumor effect in an ex vivo model of chemoresistant CRC organoids and a patient-derived organoid xenograft model. Tumor-bearing mice treated with the siRNA-delivering exosomes and hepatectomy showed ideal overall survival. Our results provide a therapeutic target and represent a possible therapeutic alternative for patients with CRC and distant metastasis and in cases of chemoresistance.

Exosomes in tumor‐stroma crosstalk: Shaping the immune microenvironment in colorectal cancer

“…77 Lastly, given exosomes' small size and natural targeting properties, they could be engineered as drug delivery vehicles for antiangiogenic therapies. 78,79 Figure 2 illustrates the role of CRC-derived exosomes in CRC progression.…”

“…62,128,131 Exosome-mediated delivery of miR has also been shown to kill tumor cells and inhibit metastasis. 79,132,133 Beyond conventional drugs, there is an intriguing possibility that exosomes could deliver gene therapies such as siRNAs 134 or the CRISPR/Cas9 geneediting mechanism 135 directly to CRC cells. By targeting or modulating specific genes, these interventions could suppress the growth and survival of cancer cells.…”

“…In preclinical studies, delivery of engineered exosomes encapsulated with doxorubicin, oxaliplatin, or 5‐FU to kill cancer cells 62,128,131 . Exosome‐mediated delivery of miR has also been shown to kill tumor cells and inhibit metastasis 79,132,133 . Beyond conventional drugs, there is an intriguing possibility that exosomes could deliver gene therapies such as siRNAs 134 or the CRISPR/Cas9 gene‐editing mechanism 135 directly to CRC cells.…”

Exosome Heterogeneity Affects the Distal “Barrier-Crossing” Trafficking of Exosome Encapsulated Quantum Dots

“…Thus, tumorderived Exo has potent applications in the clinic as a therapeutic, diagnostic, and prognostic tool. 17,18 Exo was used back in 2011 to deliver therapeutics to the brain by intravenous injection. 19 The molecular composition and heterogeneity of Exo will implicate their biological and therapeutic effects.…”

“…Practically, tumor-derived Exo are able to modulate autocrine, juxtracrine, and paracrine signaling pathways and play an irreplaceable role in the metastatic cascade of cancer recurrence and metastasis. Thus, tumor-derived Exo has potent applications in the clinic as a therapeutic, diagnostic, and prognostic tool. , …”