Folate- and aCD47-functionalized lipid nanoparticles efficiently deliver mRNA and remodel pancreatic tumor microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and treatment-resistant malignancies, with limited efficacy to conventional treatments such as surgical resection or chemotherapy. This clinical scenario underscores the need for novel therapeutic strategies. The development of multifunctional platforms capable of targeting tumors through multiple mechanisms offers an innovative strategy to overcome this challenge. Lipid nanoparticles (LNPs) offer a versatile platform capable of efficiently delivering genetic material. Moreover, through surface functionalization it is feasible to improve LNP performance optimizing therapeutic outcomes in a single formulation. Here, we explored a dual functionalization strategy of the LNP for tumor targeting and tumor remodeling to improve treatment efficacy. LNPs were designed for delivering reporter DNA plasmid or mRNA into the PDAC cellular models Capan-2 and PANC-1. The DNA plasmid contains a pancreatic cancer-specific chimeric promoter for transcriptional specificity to PDAC cells. Besides, LNPs were functionalized with folate and an anti-CD47 antibody to both target the folate receptor in PDAC cells and block CD47-mediated immune evasion. Both pDNA and mRNA LNPs targeted PDAC cells in a dose-dependent manner, with mRNA-LNPs demonstrating more efficient transfection. Notably, LNPs functionalized with the anti-CD47 antibody increased phagocytosis in vitro, and promoted an inflammatory phenotype of M1-like macrophages in mouse Capan-2 xenografts. This combinatorial design of the formulated LNP represents an innovative therapeutic strategy and opens future perspectives in the search for effective treatments for PDAC.