摘要
Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to its aggressive nature and resistance to chemotherapy. Immunotherapies have shown promise in various cancers but are limited in PDAC due to poor drug penetration through dense stroma and systemic toxicities. Here, we developed a stroma-targeted gene delivery platform for efficient immunogene therapy in PDAC. Using an in vitro-in vivo phage display screening approach, we identified the LQT peptide, which selectively binds to fibronectin 1 (FN1) in pancreatic stellate cells (PSCs), key mediators of PDAC stroma. We then engineered a lipid-dendrimer-CaP (LDCP) nanoparticle functionalized with the LQT peptide for targeted gene delivery of interleukin-2 (IL-2) plasmid DNA (pDNA). This design improves delivery to PSCs, enhances nanoparticle accumulation and penetration in PDAC, and facilitates endosomal escape and effective nuclear entry through its pH-responsive calcium phosphate core and thymine-capped polyamidoamine (PAMAM) dendrimers. The production of IL-2 significantly amplifies CD8 T cell infiltration and activation, counteracting the immunosuppressive microenvironment. When combined with checkpoint inhibitors such as anti-PD-1 antibodies or co-stimulatory molecules like OX40 ligand (OX40L), this gene therapy strategy leads to substantial suppression of PDAC progression. This stroma-targeted immunogene therapy shows significant promise as a safe and effective approach for PDAC treatment.
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A stroma-targeted nanoplatform delivers interleukin-2 genes specifically to pancreatic tumors, transforming stromal fibroblasts into cytokine-producing “immune hubs.” This approach enhances local T cell activation, improves the efficacy of checkpoint blockade or OX40 agonists, and suppresses both primary and metastatic pancreatic cancer, offering a safe and effective immunogene therapy strategy.