A Spatially Directed Microneedle Patch Enables Intratumoral Co-Delivery of FOLFIRINOX, Surufatinib, and Anti-PD-1 for Chemo-Immunotherapy of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC), a lethal malignancy with a 5-year survival of 13%, faces limited therapeutic efficacy due to fibrotic barriers that block drug access to the therapeutic site, systemic toxicity of conventional chemotherapy, and an immunosuppressive tumor microenvironment (TME). Therapeutic agents with different functions, including FOLFIRINOX (FFX), surufatinib (SUR), and anti-PD-1 (αPD-1), are co-administered to tumors in animal models using microneedle (MN) patches to achieve site-targeted synergistic efficacy. The core-shell MN structure is used, with the outer layer providing rapid FFX delivery and the inner layer providing sustained release of SUR and αPD-1. Compared with intratumoral drug injection and traditional systemic administration, MN patch-mediated administration markedly suppresses tumor growth and liver metastasis at lower doses, reduces systemic drug exposure and toxicity, and prolongs intratumoral drug retention. In addition, the MN patch-mediated intratumoral co-delivery reshapes the TME by boosting CD8+ T cells infiltration, inhibiting Foxp3+ regulatory T cells, and reducing CD206+ tumor-associated macrophages infiltration, resulting in downregulation of tumor epithelial-mesenchymal transition and increased tumor cell apoptosis. In summary, MN patch-mediated delivery of therapeutic agents provides sufficient intratumoral doses and minimizes systemic toxicity through multiple microchannels, suggesting that MN patch co-delivery is a promising adjunct for enhancing efficacy against PDAC.