Colonization of engineered bacteria enhanced lipid nanomedicine accumulation in tumors for sonodynamic immunotherapy

Lipid nanoparticles (LNPs) demonstrate liver-accumalating properties, enhancing drug delivery to hepatic tissues. This localized enrichment reduces systemic toxicity and mitigates drug resistance. However, critical limitations such as off-target effects, rapid clearance, and poor specificity hinder their clinical translation. Inspired by the tumor-targeting ability of bacteria, we constructed a multifunctional engineered bacteria system combining LNPs with probiotics by electrostatic adsorption. Specifically, the surface of <i>Bifidobacterium longum</i> (BL) was modified with sorafenib-loaded LNPs (designated PSI LNPs), enabling precise delivery of lipid nanomedicines to tumor sites. Meanwhile, ultrasound irradiation facilitated drug release and improved efficacy. On the one hand, we used fluorescence imaging to observe and monitor live-engineered bacteria. Compared to the single PSI LNPs group, the tumor accumulation of lipid nanomedicines loaded with engineered bacteria exhibited a 66 % increase. The results demonstrated that the engineered bacteria not only augmented the accumulation of nanomedicines but also prolonged the retention time for a sustained effect on the tumor. On the other hand, we further explored synergistic immune system activation by <i>Bifidobacterium</i> and sonodynamic therapy, which stimulated dendritic cell maturation, T cell infiltration, and CD8⁺ T cell activation. In conclusion, this delivery strategy of engineered bacteria targeting the tumor microenvironment is expected to overcome the limitations of conventional LNPs and provide a promising approach for treating hepatocellular carcinoma.