Engineered a dual-targeting biomimetic nanomedicine for pancreatic cancer chemoimmunotherapy
Meng Wang, Qida Hu, Junmin Huang, Xinyu Zhao, Shiyi Shao, Fu Zhang, Zhuo Yao, Ping Yuan, Tingbo Liang
Abstract
The therapeutic effect of chemotherapeutics such as gemcitabine against pancreatic cancer is considerably attenuated by immune-suppressive tumor microenvironment. Improvement of chemotherapeutic efficacy by targeting tumor-associated macrophage and reprograming tumor microenvironment to enhance their efficacy may become a promising strategy. To this end, we developed a biomimetic dual-targeting nanomedicine (PG@KMCM) where gemcitabine-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles are coated with a layer of bioengineered cancer cell membrane that stably expresses peptides targeting M2-like macrophages (M2pep) while reserving tumor-associated antigens (TAAs). The PG@KMCM nanomedicine enables the simultaneous targeted delivery of gemcitabine to pancreatic tumor sites and TAMs to potentiate its therapeutic effects. Furthermore, the combination of an immune checkpoint inhibitor (PD-L1 antibody) with PG@KMCM synergistically enhanced the anti-tumoral effect by reprogramming the immune-suppressive tumor microenvironment, including the elimination of PD-L1-positive macrophages and the downregulation of PD-L1 expression. Our study proved dual-targeting PG@KMCM nanomedicine in combination with PD-L1 immune checkpoint inhibitor therapy is able to effectively reprogram the tumor microenvironment and kill pancreatic cancer cells to enhance overall therapeutic potential.