Nanobooster-encapsulated hybrid RNA as anti-tumor viral mimicry

Abstract

Abstract Innate sensing of viral RNA analogs represents a promising tool for cancer intervention, yet the tumor microenvironment (TME) renders tumor cells and immune cells unresponsive to exogenous innate stimuli. Herein, we design a hybrid RNA yielding both endogenous retrovirus and exogenous viral signature for orchestrated immune activation. Additionally, we encapsulate the RNA in a TME-responsive nanobooster, which generates oxygen to awaken hypoxia-mediated dormancy of viral RNA sensors. This two-in-one viral mimicry demonstrates synergistic effects on the production of type I interferons (α and β), maturation of dendritic cells and apoptosis of cancer cells, and further stimulates anti-tumor T cell immunity and memory. Significantly, monotherapy with the viral mimicry potently suppresses tumor growth, post-surgical relapse and metastasis in murine liver and breast cancer models, and exhibits long-term resistance against tumor re-challenge. Our study thus provides a straightforward but effective strategy for self-amplification of innate immunity in cancer therapy.