Aquaporin encoding mRNA mediated water bomb vaccine for cancer immunotherapy

Abstract

Inducing immunogenic cell death (ICD) in tumors is a promising strategy for activating systemic antitumor immunity. However, most ICD approaches rely on chemotherapeutic or physical agents that pose challenges in controllability and biosafety. Here, we report a drug-free, mRNA-based strategy that induces a novel form of ICD via a “water bomb” effect. By delivering aquaporin mRNA into tumor cells using nucleic acid nanocarriers, aquaporins are expressed and embedded in the tumor cell membrane. Upon modulation of the transmembrane osmotic gradient, water influx is rapidly amplified through aquaporin channels, leading to extreme cellular swelling, complete membrane rupture, and explosive tumor cell lysis. This unique form of endogenously driven mechanical ICD elicits potent immune activation by concurrently releasing a full spectrum of damage-associated molecular patterns (DAMPs), tumor-specific antigens, and neoantigens in situ, thereby promoting efficient activation of bone marrow-derived dendritic cells (BMDCs) and enhancing subsequent antigen presentation. In a murine melanoma model, this strategy significantly inhibited the growth of both primary and distant tumors, as well as lung metastases. Similarly, in a breast cancer mouse model, it markedly suppressed the growth of subcutaneous tumors. With excellent biocompatibility, tunability, and immune potency, this “water bomb” based approach offers a conceptually new paradigm for cancer immunotherapy via endogenously driven mechanical ICD.