Enhancing Pancreatic Ductal Adenocarcinoma Immunotherapy under Stress through Sympathetic Nerve-T cell Interaction Blockade via Co-delivery of β-Blockers and aTIM-3 with Ultrasound-Responsive Bionic Nanoparticles.

Pancreatic ductal adenocarcinoma (PDAC), a refractory cold tumor, is characterized by a dense extracellular matrix (ECM) and stress-triggered neuroimmune crosstalk, which cause T cell exhaustion and poor efficacy of anti-T cell immunoglobulin and mucin domain-3 antibody (aTIM-3) monotherapy. Here, we report a sucrose-hybridized, Pan02 pancreatic tumor cell membrane-coated ultrasound (US)-responsive biomimetic nanocarrier (CT@SM) co-loading carvedilol (β-blocker) and aTIM-3. The Pan02 tumor cell membrane shell enables homologous tumor targeting, prolonged circulation, and reduced off-target distribution, while intercalated sucrose modulates vesicle acoustic impedance to generate US-triggered inertial cavitation. US activates cavitation to disrupt the ECM and co-releases cargos deep in tumors: carvedilol relieves norepinephrine-mediated T cell exhaustion, and aTIM-3 suppresses M2-type tumor-associated macrophages. Consequently, compared to free aTIM-3, up to an 11.23-fold increase of aTIM-3 in the tumor region was obtained in the CT@SM + US group. Immunotherapy efficacy was significantly enhanced by reactivating T cells, leading to suppressed tumor growth and prolonged survival in the PDAC mice stress model. Overall, this study offers a promising strategy based on a dual-modified biomimetic acoustic delivery platform for immunotherapy in PDAC and other cold tumors.