Theranostic nanosystem mediating cascade catalytic reactions for effective immunotherapy of highly immunosuppressive and poorly penetrable pancreatic tumor

Abstract

The dense desmoplastic stroma and immunosuppressive microenvironment of pancreatic cancer hinder the penetration of drugs and induce a considerable resistance to conventional chemoradiotherapy. Although nanomedicine has recently shown attractive potential in cancer immunotherapy, it remains a great challenge to achieve efficient drug delivery and potent immune activation. Here, a stimuli-responsive nanosystem, comprising superparamagnetic iron oxide nanocrystals and nitric oxide (NO) donors, was developed for in-situ triggered catalytic cascade reaction to produce abundant free radicals and remodel the anti-tumor immunity. The nanosystem was activated in the tumor microenvironment to produce NO which dilated the tumor vasculature for efficient drug delivery, and the iron oxide nanocrystals catalyzed the reaction of NO to generate reactive oxygen-nitrogen species (RONS) with high cytotoxicity. Moreover, owing to the catalytic cascade reactions mediated by the nanosystem, the tumor associated macrophages (TAMs) were converted to a proinflammatory M1 phenotype and tumor infiltration of effector T cells was promoted to result in potent anti-tumor immunotherapy which could be readily monitored with magnetic resonance imaging (MRI).