EGFR-antibody-decorated cancer-cell-membrane-coated MOF nanoplatform enables targeted delivery of the STING agonist diABZI for pancreatic cancer immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) has limited immunotherapeutic effect because of poor drug penetration and tumor immunosuppression. Activation of the stimulator of interferon genes (STING) pathway may promote antitumor immunity, but systemic administration of STING agonists is constrained by inadequate tumor accumulation. Epidermal growth factor receptor (EGFR) is frequently overexpressed in PDAC and is closely associated with tumor growth, invasion, and treatment resistance. Herein, we developed an EGFR-antibody-decorated cancer-cell-membrane-coated metal-organic framework (MOF) nanoplatform loaded with the STING agonist diamidobenzimidazole (diABZI) (EM@MOF/diABZI) for targeted pancreatic cancer immunotherapy. This nanoplatform consists of an acid-responsive diABZI loaded MOF core and an EGFR-antibody-functionalized pancreatic cancer-cell-membrane shell. The nanoplatform displayed preserved membrane-associated proteins and EGFR-binding activity, pH-dependent diABZI release, significantly enhanced cellular uptake and preferential tumor accumulation. In a subcutaneous Pan02 pancreatic cancer mouse model, EM@MOF/diABZI produced greater tumor-growth inhibition and improved survival. Mechanistically, targeted diABZI delivery increased intratumoral p-STING expression and elevated the levels of IFN-β, CXCL10, TNF-α, IL-6, and IFN-γ, accompanied by enhanced infiltration of CD4+ and CD8+ T cells. No obvious histopathological abnormalities or substantial systemic toxicity were observed. Therefore, this nanoplatform provides a promising strategy for enhancing the therapeutic effect of STING agonists for pancreatic cancer immunotherapy.