Turmeric extracellular vesicles-derived "all-in-one" nanoagent enables full-cycle synergistic immunomodulation of lung cancer.

Abstract

Lung cancer's metastatic propensity and recurrence prevalence necessitate innovative immunotherapy strategies beyond conventional single-mode regulation. We engineered low-capacity turmeric-derived extracellular vesicles (TEVs) that integrated with zeolitic imidazolate framework-8 (ZIF-8) to construct an "all-in-one" nanoagent, addressing both high drug loading nanocarriers production and immunologically cold tumor challenges. The system co-delivered chlorin e6 (Ce6) and PD-L1 siRNA, while exploited TEVs' inherent curcumin for Wnt/β-catenin pathway inhibition. Ce6-mediated photodynamic therapy (PDT) induced immunogenic cell death (ICD), releasing damage associated molecular patterns (DAMPs) to activate antigen-presenting cells (APCs). Compared with control groups, artificial intelligence model confirmed the role of curcumin in enhancing immune infiltration by 6.1-fold. PD-L1 siRNA synergistically downregulates the checkpoint expression with a 66 % reduction <i>in vivo</i> to prevent the immune escape. This coordinated strategy achieved full-cycle immunomodulation: (1) ICD initiated antigens release, (2) Wnt/β-catenin pathway inhibition drived T cell infiltration, and (3) PD-L1 blockade receded the immune escape. <i>In vivo</i> results demonstrated that 64 % primary tumor suppression and 81 % metastasis reduction versus monotherapy groups. The ZIF-8@TEV hybrid platform exhibited 12.8 % payload loading efficiency, surpassing liposomal carriers by 4.7-fold. This study established a scalable nanoengineering approach to transform immunosuppressive tumors into immunotherapy-responsive targets through a full-cycle immune coordination.