Unleashing the power of precision drug delivery: Genetically engineered biomimetic nanodrugs incorporating liposomal polypharmacy against multidrug-resistant bacteria

To date, the antibiotics combination therapy is one of the most important approaches to eradicate the multidrug-resistant (MDR) bacteria. Besides, in vivo antibiotics delivery systems also play an essential role in improving the targeting and efficacy of antimicrobial therapies. Herein, we described a promising combination strategy by using an antibiotic medication (colistin) together with its adjuvant H-89 to treat MDR bacterial infections. Meanwhile, genetically engineered outer membrane vesicle (OMV) with single chain fragment variable (scFv) of anti-PcrV antibody (OMV-antiPAO1) was coated to liposomal colistin and H-89 to produce biomimetic nanodrugs (LNP-H89-Coli@OMV). In particular, the targeting, high-efficient delivery and enhanced killing abilities of LNP-H89-Coli@OMV to MDR bacteria is attributed to the OMV-antiPAO1, which show the similar structure and function to Gram-negative MDR bacteria and can express targeting antibody toward pcrV by the fusion of coding region with ClyA (a surface protein in E. coli). Antibacterial experiments demonstrated that LNP-H89-Coli@OMV was able to completely eliminate the persistent Pseudomonas aeruginosa PAO1 (>99.999999 % killing efficiency), whereas in vivo tests showed that MDR infections were totally cured by the present liposomal drugs for the first time. Therefore, this pilot study opened a new avenue for the development of multifunctional targeted drugs against MDR infection, particularly the persistent PAO1.