In Situ Sprayed Nanovaccine Suppressing Exosomal PD-L1 by Golgi Apparatus Disorganization for Postsurgical Melanoma Immunotherapy

Theanti-PD-L1 immunotherapy has shown promise in treatingcancer.However, certain patients with metastatic cancer have low responseand high relapse rates. A main reason is systemic immunosuppressioncaused by exosomal PD-L1, which can circulate in the body and inhibitT 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 GENPscan accumulate in tumors through homotypic targeting and effectivelydeliver retinoic acid, inducing disorganization of the Golgi apparatusand a sequence of intracellular events including alteration of endoplasmicreticulum (ER)-to-Golgi trafficking and subsequent ER stress, whichfinally 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 withanti-PD-L1 treatment in the sprayable in situ hydrogel,we have successfully realized a low recurrence rate and substantiallyextended survival periods in mice models with incomplete metastaticmelanoma resection. ISSN:1936-0851 ISSN:1936-086X