<i>In Situ</i> Sprayed Nanovaccine Suppressing Exosomal PD-L1 by Golgi Apparatus Disorganization for Postsurgical Melanoma Immunotherapy
Hao Ye, Kaiyuan Wang, Jian Zhao, Lu Qi, Menglin Wang, Bingjun Sun, Yang Shen, Hongchen Liu, Salvador Pané, Xiangzhong Chen, Zhonggui He, Jin Sun
Abstract
The anti-PD-L1 immunotherapy has shown promise in treating cancer. However, certain patients with metastatic cancer have low response and high relapse rates. A main reason is systemic immunosuppression caused by exosomal PD-L1, which can circulate in the body and inhibit T cell functions. Here, we show that Golgi apparatus-Pd- l1 –/– exosome hybrid membrane coated nanoparticles (GENPs) can significantly reduce the secretion of PD-L1. The GENPs can accumulate in tumors through homotypic targeting and effectively deliver retinoic acid, inducing disorganization of the Golgi apparatus and a sequence of intracellular events including alteration of endoplasmic reticulum (ER)-to-Golgi trafficking and subsequent ER stress, which finally disrupts the PD-L1 production and the release of exosomes. Furthermore, GENPs could mimic exosomes to access draining lymph nodes. The membrane antigen of PD- l1 –/– exosome on GENPs can activate T cells through a vaccine-like effect, strongly promoting systemic immune responses. By combining GENPs with anti-PD-L1 treatment in the sprayable in situ hydrogel, we have successfully realized a low recurrence rate and substantially extended survival periods in mice models with incomplete metastatic melanoma resection.