Spatiotemporal STING activation via engineered bacterial vesicles enables safe and efficient cancer immunotherapy

The activation of stimulator of interferon genes (STING) pathways holds immense potential for cancer immunotherapy. Nevertheless, the challenge lies in achieving precise and efficient STING activation within tumors while avoiding systemic immunotoxicity. Here, we develop a novel nanotherapeutic platform, termed HAL@SyBVs, by simply electroporating FDA-approved prodrug 5-aminolevulinate hydrochloride (HAL) into the synthetic bacterial vesicles (SyBVs), which allows for the spatiotemporal orchestration of STING pathways. Following systemic injection, HAL@SyBVs target tumor tissues, where HAL induces the confined biosynthesis and accumulation of sonosensitizer protoporphyrin IX (PpIX) within mitochondria. Upon ultrasound irradiation, PpIX-induced reactive oxygen species (ROS) trigger the release of double-stranded DNA (dsDNA), thereby achieving precise STING activation. Simultaneously, SyBVs enhance STING signaling by impeding its degradation, thereby amplifying the immune response. This intelligent synergy effectively ameliorates the immunosuppressive tumor microenvironment and elicits a robust antitumor T cell immune response, resulting in comprehensive tumor regression without apparent adverse effects.