In situ released bacterial membrane vesicles activate the STING pathway via boosting the intracellular DNA pool for immunotherapy

Abstract

The cGAS-STING pathway represents an important target for amplifying immune responses in immunotherapy. This pathway is activatable by either endogenous or exogenous dsDNA. However, the effectiveness of these dsDNA sources is constrained by inadequate reactive oxygen species or limited sequence length. A unilateral source of endogenous or exogenous dsDNA may result in inadequate accumulation of the DNA pool, thereby restricting immune responses. Herein, a near-infrared light (NIR)-responsive nanoplatform has been developed by integration of bacterial outer membrane vesicles (OMVs) and high-entropy alloys (HEAs) into a hydrogen-bonded organic framework (HOF) to enhance intracellular DNA pools for activating the tumoral STING pathway and immunotherapy. The encapsulation of OMVs by HOFs dampens nonspecific activation of STING and systemic inflammation induced by lipopolysaccharides. Moreover, HEAs possess the capability to decompose HOFs, facilitating the intratumoral release of OMVs upon NIR exposure. The exogenous bacterial dsDNA present in OMVs, coupled with the endogenous dsDNA released by HEAs via peroxidase (POD)-like activity, collectively augments the DNA pool within tumors, fostering the activation of the STING signaling pathway. This work offers a paradigm for the design of a nanoplatform to stimulate the STING signaling pathway by enhancing the DNA pool for immunotherapy.