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A targeted systemic delivery platform of therapeutic modified mRNA and modRNA-derived antibodies for precision triple negative breast cancer treatment.

ABSTRACT: modified mRNA (modRNA) showed high efficacy and safety when used for COVID-19 mRNA vaccines. Upon vaccination, any cell receiving modRNA contributed to efficient expression of antigens resulting in robust immune response. However, in most disease settings it is crucial to restrict translation of therapeutic genes to clinically relevant cells. Here, we designed a breast cancer-Specific modRNA Translation system (bcSMRTs) for enriched gene expression in tumors after systemic delivery with lipid nanoparticles (LNP). Intravenous delivery of bcSMRTs led to a 114-fold increase in tumor-specific signal and a 383-fold decrease in other organs compared to regular modRNA. For therapeutic targeting, we designed modRNA-derived antibodies (modRNabs) in which host cells serve as a bioreactor to produce anti-checkpoint inhibitor antibodies such as anti-cytotoxic T lymphocyte antigen-4 (αCTLA-4). Our results show that αCTLA-4 modRNab inhibited tumor growth by 37% while bcSMRTs carrying Pip4K2c (Phosphatidylinositol-5-phosphate 4-kinase, type II, gamma) gene did so by 25%. Importantly, combining the two reduced tumor size by 75% and reorganized the immune cell landscape in a poorly immunogenic 4T1 model of breast cancer. The modular platform we created to evaluate and screen gene-based treatments in a breast cancer model can easily be adjusted to other types of cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE239577 | GEO | 2023/12/31

REPOSITORIES: GEO

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Project description:1H NMR is used to detect alterations in metabolites and their linkage to metabolic processes in a number of pathological conditions including breast cancer. Inositol 1, 4, 5 trisphosphate (IP3R) receptor is an intracellular calcium channel known to regulate metabolism and cellular bioenergetics. Its expression is up regulated in a number of cancers. However, its linkage to metabolism in disease conditions has not been evaluated. This study was designed to determine the association if any, of these metabolites with altered expression of IP3R in breast cancer. We used 1H NMR to identify metabolites in the serum of breast cancer patients (n = 27) and performed Real-time Polymerase Chain Reaction analysis for quantifying the expression of IP3R type 3 and type 2 in tissues from breast cancer patients (n = 40). Principal Component Analysis (PCA) and Partial Least Square-Discriminant Analysis (PLS-DA) clearly distinguished patients with high/low IP3R expression from healthy subjects. The present study revealed high expression of IP3R type 2 and type 3 in human breast tumor tissue compared to adjacent non-tumorous tissue. Moreover, patients with = 2-fold increase in IP3R (high IP3R group) had significantly higher concentration of metabolic intermediates compared to those with < 2-fold increase in IP3R (low IP3R group). We observed an increase in lipoprotein content and the levels of metabolites like lactate, lysine and alanine and a decrease in the levels of pyruvate and glucose in serum of high IP3R group patients when compared to those in healthy subjects. Receiver operating characteristic (ROC) curve analysis was performed to show the clinical utility of metabolites. In addition to the human studies, functional relevance of IP3Rs in causing metabolic disruption was observed in MCF-7 and MDA MB-231 cells. Results from our studies bring forth the importance of metabolic (or metabolomics) profiling of serum by 1H NMR in conjunction with tissue expression studies for characterizing breast cancer patients. The results from this study provide new insights into relationship of breast cancer metabolites with IP3R.

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A targeted systemic delivery platform of therapeutic modified mRNA and modRNA-derived antibodies for precision triple negative breast cancer treatment.

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