Lipid nanoparticle-mediated mRNA/siRNA dual-bioengineered dendritic cell vaccines combined of PD-1/PD-L1 blockade for boosting tumor immunotherapy

Abstract

DC vaccines occupy a pivotal position in the realm of cancer treatment, leveraging the immune system to precisely target and effectively eliminate tumor cells. However, current challenges in tumor DC vaccine development include issues such as limited efficacy and potential upregulation of immunosuppressive molecules like PD-L1 on tumor cells. Herein, we employed microfluidic technology to fabricate lipid nanoparticles (LNPs) that simultaneously encapsulate OVA mRNA (mOVA), encoding the model antigen OVA, and siRNA targeting PD-L1. The LNP/mOVA/siPD-L1 nanoparticles were utilized to transfect bone marrow-derived dendritic cells (BMDCs) to construct dual-bioengineered DC vaccines. Subsequently, the efficacy of the dually bioengineered DC vaccines was verified in both prophylactic and therapeutic tumor vaccine models. The upregulation of PD-L1 protein expression on the surface of tumor cells was further blocked by combination of anti-PD-L1 antibody therapy. Notably, the combined therapy achieved complete tumor suppression and the rechallenge experiments demonstrated the tumor immune memory effect induced by the combined therapy, highlighting its potential to elicit long-lasting immunity against cancer. Overall, our findings suggest that this combined therapy holds significant promise for the treatment, metastasis prevention, and recurrence management of tumors, with potential clinical application value in the future.