T‑Cell Immunoreceptor with Ig and Immunoreceptor Tyrosine-Based Inhibitory Motif Domains/Cluster of Differentiation 40 Cellular Nanovesicles Carrying Oxaliplatin Exhibited Superior Pancreatic Cancer Cells Therapy.

Profound chemoresistance and a highly immunosuppressive tumor microenvironment (TME) contribute to the high mortality rate of pancreatic ductal adenocarcinoma (PDAC). The overexpression of CD155 in PDAC facilitates its binding to the inhibitory receptor T-cell immunoreceptor with Ig and ITIM domains (TIGIT) on T-cells, thereby inducing immunosuppression. Herein, a biomimetic theranostic platform was constructed by encapsulating oxaliplatin (OXA)-loaded melanin nanoparticles (MNS) within engineered nanovesicles overexpressing TIGIT and cluster of differentiation 40 (CD40). These NVs serve a dual-modal function: they competitively antagonize the TIGIT/CD155 axis to bypass immune checkpoints and simultaneously trigger the CD40/CD40L pathway to provide potent costimulatory signals. This synergistic mechanism reverses T-cell exhaustion and enhances CD8 T-cell infiltration, effectively remodeling the "cold" PDAC microenvironment. Furthermore, the integration of Cy5.5 and OXA-loaded MNS core enables drug delivery and real-time monitoring via fluorescence and magnetic resonance imaging (MRI). In vivo studies demonstrated that MO@Ti40 NVs significantly impede tumor progression with markedly reduced systemic toxicity compared to free OXA. By integrating targeted chemotherapy with comprehensive immune reprogramming, this platform offers a promising therapeutic strategy for refractory malignancies like PDAC.