Delivery of 5-fluorouracil modified MicroRNAs by fucoidan-based magnetic nanoparticles to enhances tumor-localized immunotherapy and chemotherapy

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with an exceedingly low survival rate. It is characterized by a dense fibrotic stroma that impedes drug penetration and limits the efficacy of conventional therapies. Consequently, combining gene therapy with immunotherapy has been proposed as an innovative approach for the treatment of PDAC. Here, we designed a multifunctional nanocarrier (Fuc@miR MNPs), composed of a magnetic core surrounded by a polyethyleneimine/fucoidan shell, as a vehicle for the simultaneous targeted delivery of 5-fluorouracil (5-FU) embellished miRNA-15a mimics and fucoidan into PDAC cells. Fuc@miR MNPs have good miRNA encapsulation capacity and stable transmission efficiency. In vitro, Fuc@miR MNPs inhibited the expression of YAP-1 and Bcl-2 and released 5-FU to kill tumor cells and programmed tumor-associated macrophages (TAMs) to the M1 phenotype. In vivo, Fuc@miR MNPs were simultaneously enriched at tumor sites via magnetic navigation and p-selectin to reduce off-target effects and toxicities. Fuc@miR MNPs exerted promising antitumor activity by down-regulating the expression of oncogenes YAP-1 and Bcl-2, and alleviating the immunosuppressive tumor microenvironment. Thus, Fuc@miR MNPs are promising nanomedicines compatible with miRNA gene therapy and immunomodulation to kill tumors and improve the immunosuppressive tumor microenvironment for multidimensional treatment of PDAC.