Orally Deliverable Engineered Porphyrin Nanohybrids Activate the cGAS-STING Axis and Enable Fusobacterium-Specific Targeting for Robust Immune Remodeling and Colorectal Cancer Regression

The susceptibility of colorectal cancer (CRC) cells to <i>Fusobacterium nucleatum</i> (<i>F. nucleatum</i>) infection pose significant challenges to CRC treatment and prevention. This study addresses these challenges by mobilizing cGAS/STING axis activation and <i>F. nucleatum</i>-specific targeting, thereby achieving a multimodal treatment strategy for reversing the immunosuppressive microenvironment (ITM) and achieving targeted anti-<i>F. nucleatum</i> therapy. Specifically, a hybrid nanoplatform CuPpIX@HM was engineered using <i>Escherichia coli</i> and tumor cell membranes encapsulating ultrasound (US) stimulation-responsive copper protoporphyrin IX (CuPpIX). This design enables the precise accumulation of the nanoplatform at tumor sites following oral administration. Notably, upon US activation, CuPpIX generates a high level of reactive oxygen species (ROS), selectively eradicating <i>F. nucleatum</i> and exerting potent antitumor effects. Meanwhile, bacterial membrane components activate the cGAS/STING signaling pathway, effectively reversing the ITM, enhancing systemic antitumor immunity. Importantly, CuPpIX@HM exerts minimal disruption to healthy intestinal microbiota and remarkably increases the level of probiotics. In both orthotopic and liver metastasis, CRC models demonstrated that this strategy could significantly inhibit tumor growth and metastasis. Collectively, our study presents a highly targeted multimodal nanotherapy that holds strong potential to improve CRC treatment outcomes through the precision modulation of <i>F. nucleatum</i> and immune activation.