Nanoparticle Delivery of miR-122 Inhibits Colorectal Cancer Liver Metastasis

Abstract

Liver metastasis is a leading cause of cancer morbidity and mortality. Thus, there has been strong interest in the development of therapeutics that can effectively prevent liver metastasis. One potential strategy is to utilize molecules that have broad effects on the liver microenvironment, such as miR-122, a liver-specific miRNA that is a key regulator of diverse hepatic functions. Here we report the development of a nanoformulation miR-122 as a therapeutic agent for preventing liver metastasis. We engineered a galactose-targeted lipid calcium phosphate (Gal-LCP) nanoformulation of miR-122. This nanotherapeutic elicited no significant toxicity and delivered miR-122 into hepatocytes with specificity and high efficiency. Across multiple colorectal cancer liver metastasis models, treatment with Gal-LCP miR-122 treatment effectively prevented colorectal cancer liver metastasis and prolonged survival. Mechanistic studies revealed that delivery of miR-122 was associated with downregulation of key genes involved in metastatic and cancer inflammation pathways, including several proinflammatory factors, matrix metalloproteinases, and other extracellular matrix degradation enzymes. Moreover, Gal-LCP miR-122 treatment was associated with an increased CD8+/CD4+ T-cell ratio and decreased immunosuppressive cell infiltration, which makes the liver more conducive to antitumor immune response. Collectively, this work presents a strategy to improve cancer prevention and treatment with nanomedicine-based delivery of miRNA. Significance: Highly specific and efficient delivery of miRNA to hepatocytes using nanomedicine has therapeutic potential for the prevention and treatment of colorectal cancer liver metastasis.

MicroRNA-122 in human cancers: from mechanistic to clinical perspectives

“…Their research found that miR-122 transmission was linked to the downregulation of essential genes implicated in the inflammatory routes that lead to cancer metastasis, namely several pro-inflammatory factors, matrix metalloproteinases, and other extracellular matrix breakdown enzymes. The liver is more receptive to an antitumor immunological reaction as a result of Gal-LCP miR-122 therapy because of its enhanced CD8 + /CD4 + T-cell ratio and reduced cell-infiltrated immunosuppression [ 103 ]. Additionally, perfluoropentane/C9F17-PAsp(DET)/miR-122/poly(glutamic acid)-g-MeO-poly(ethylene glycol) (PGA-g-mPEG) ternary nanodroplets (PFP-TNDs/miR-122), were created by Guo et al to transfer miR-122 for the treatments of HCC.…”

Potential Roles of miRNAs in Acute Rejection for Vascularized Composite Allotransplantation

“…[19][20][21] They play multiple roles in various physiological processes, including neovascularization, immune regulation, and the stress response. 22,23 Therefore, it is possible that miRNAs are also involved in acute rejection during VCA. To this end, we sequenced the miRNAs in control and transplanted muscle tissues in a rodent model of VCA, and identified 28 differentially expressed miRNAs.…”

SMAD4 Loss Induces c-MYC–Mediated NLE1 Upregulation to Support Protein Biosynthesis, Colorectal Cancer Growth, and Metastasis

“…A nanoparticle-based delivery of these molecules effectively mediates RNA interference in cancer cells, and nano-carriers can be optimized to meet the therapeutic requirements of a specific disease (reviewed in ref. 65 ), such as colorectal cancer liver metastasis ( 66 ).…”