Genetically engineered hybridized OMVs for treatment of implant-associated infections and relapse prevention through host immunomodulation
Implant-associated infections (IAIs) are refractory to elimination and local immunosuppressive microenvironment exacerbates the therapeutic difficulty, further causing the persistence and relapse. Therefore, exploring immune-strengthening therapeutics holds great promise to reverse suppressive host immunity and thoroughly eradicate chronic or repetitive infections. Bacterial outer membrane vesicles (OMVs) emerge as a potential immunostimulatory candidate, which is however, still suffer from lacking active targeting capability and non-specific systemic inflammatory storms. Herein, we genetically engineered bone marrow-derived mesenchymal stem cells (BMSCs) to express CXCR4 and isolated the cell membranes (mBMSCCXCR4) to hybridize them with OMVs derived from Escherichia coli (E. coli) to finally produce nanovesicles (mBMSCCXCR4@OMV). Due to the hybridized membrane structure of mBMSCCXCR4, the resulting nanovesicles generated excellent targeting capability towards bone marrow and were obviously uptaken by bone marrow-derived macrophages, triggering the efficient transition to pro-inflammatory M1 status through TLR/NF-?B pathway. This alteration promoted its innate bactericidal capacity and antigen presentation. Subsequent activation of T cells and B cells derived from bone marrow and inhibition of myeloid-derived suppressor cells (MDSCs) facilitated the in vivo clearance of infections through adaptive immunity via mouse models. In addition, mBMSCCXCR4@OMV also boosted  memory B cells and bacteria-specific antibody responses. Together, this study warrants our mBMSCCXCR4@OMV to eradicate complicated IAIs and provides a whole-stage protection to prevent the postsurgical relapse, marking a significant immunotherapeutic advancement in the post-antibiotic era. Overall design: RAW264.7 cells were treated with PBS or mBMSCCXCR4@OMV (50 µg mL-1).