Molecular therapy : the journal of the American Society of Gene TherapySep 29, 2025

Gene delivery to supportive tissue for effective immune therapy against pancreatic cancer

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 7, 2026

Abstract

A stroma-targeted gene delivery platform may enhance the treatment efficacy of pancreatic ductal adenocarcinoma (PDAC).

The LQT peptide selectively binds to fibronectin 1 in pancreatic stellate cells, which are important in PDAC stroma.
A lipid-dendrimer-CaP nanoparticle was engineered to deliver interleukin-2 plasmid DNA specifically to these cells.
This delivery system improves nanoparticle accumulation and penetration in PDAC while facilitating effective gene transfer.
Production of interleukin-2 leads to increased infiltration and activation of CD8 T cells, potentially countering the immunosuppressive environment.
Combining this gene therapy with checkpoint inhibitors may significantly suppress the progression of PDAC.

Simplified

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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Declaration of interests The authors declare no competing interests.

PubMed

Gene delivery to supportive tissue for effective immune therapy against pancreatic cancer

Abstract

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Funding

Competing interests

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Abstract

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