Hybrid nanoparticle-mediated simultaneous ROS scavenging and STING activation improve the antitumor immunity of in situ vaccines.

Abstract

In situ vaccine (ISV) is a versatile and personalized local immunotherapeutic strategy. However, the compromised viability and function of dendritic cells (DCs) in a tumor microenvironment (TME) largely limit the therapeutic efficacy. We designed a hybrid nanoparticle-based ISV, which accomplished superior cancer immunotherapy via simultaneously scavenging reactive oxygen species (ROS) and activating the stimulator of interferon genes (STING) pathway in DCs. This ISV was constructed by encapsulating a chemodrug, SN38, into diselenide bond-bridged organosilica nanoparticles, followed by coating with a Mn²⁺-based metal phenolic network. We show that this ISV can activate the STING pathway through Mn²⁺ and SN38 comediated signaling and simultaneously scavenge preexisting H₂O₂ in the TME and Mn²⁺-catalyzed •OH by leveraging the antioxidant property of diselenide and polyphenol. This ISV effectively activated DCs and protected them from oxidative damage, leading to remarkable downstream T cell activation and systemic antitumor immunity. This work highlights a nanoparticle design that manipulates DCs in the TME for improving the ISV.