Lipid Nanoparticle-Based αHTRA1 mRNA Improves Pancreatic Ductal Adenocarcinoma Redox Microenvironment by Suppressing HTRA1/HIF-1 Signaling.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with an inferior prognosis, and currently, there is a lack of effective treatment options. In immunotherapy, messenger RNA (mRNA)-based drugs, especially mRNA vaccines, have shown great potential in recent years. Previous research has found that high-temperature requirement protein A1 (HTRA1) is upregulated in PDAC and is a key factor in disease progression. Based on this key discovery, we have developed an mRNA drug based on lipid nanoparticles (LNP), which utilizes the efficient delivery capability of LNP to achieve precise delivery of antibodies targeting HTRA1 in vivo, thereby directly inhibiting the expression of HTRA1 in tumor cells. As a delivery carrier, LNP not only improves the stability and bioavailability of mRNA but also enhances its enrichment and release efficiency in tumor tissues. This study confirms that anti-HTRA1 (αHTRA1) mRNA can effectively inhibit the malignant phenotype of PDAC cells. Furthermore, we have established C57BL/6 wild-type (WT) and LSL-KrasG12D/+; Pdx1-Cre (KC) mouse pancreatic organoid models, and the results indicate that the drug, by inhibiting the hypoxia-inducible factor-1 (HIF-1) signaling pathway, improves the tumor microenvironment and can effectively suppress the progression of PDAC. The mRNA drugs based on LNP designed and synthesized in this study have good therapeutic potential for PDAC, providing new potential drugs for targeted therapy of PDAC.