Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis

Abstract

Sepsis, a condition caused by severe infections, affects more than 30 million people worldwide every year and remains the leading cause of death in hospitals 1,2 . Moreover, antimicrobial resistance has become an additional challenge in the treatment of sepsis 3 , and thus, alternative therapeutic approaches are urgently needed 2,3 . Here, we show that adoptive transfer of macrophages containing antimicrobial peptides linked to cathepsin B in the lysosomes (MACs) can be applied for the treatment of multi-drug resistant (MDR) bacteria-induced sepsis in mice with immunosuppression. The MACs are constructed by transfection of vitamin C lipid nanoparticles (V C LNPs) that deliver antimicrobial peptide and cathepsin B (AMP-CatB) mRNA.

Towards Robust Delivery of Antimicrobial Peptides to Combat Bacterial Resistance

“…In particular, macrophages and neutrophils, phagocytic cells acting as the first line of defence against infection, engulf bacteria within minutes of infection [56]. The engulfed bacteria are then destroyed by fusion with acidic lysosomes, which deliver digestive enzymes, bactericidal proteins (e.g., lysozyme), proton pumps, ROS and reactive nitrogen species to the phagosome [57,58].…”

“…Although phagolysosomal killing is usually quite effective, a number of bacteria, including Escherichia coli and S. aureus, have developed methods to survive this process, allowing them to reside within the cell for prolonged periods of time [56,58]. These pathogen-containing immune cells can then disseminate the bacteria throughout the body, where they can infect other tissues, thereby causing chronic or recurrent infections [56,59].…”

“…One unique approach to targeting bacterial infection is to take advantage of the innate targeting of phagocytic immune cells that spontaneously scavenge and destroy bacteria within the body [28,58,64]. For example, Xiong et al developed vancomycin-loaded nanogels covered in mannosyl ligands for targeted delivery to macrophages, which express high levels of mannose receptors [64].…”

“…Once the nanogel-containing macrophages engulfed bacteria at the site of infection, the nanogel's polyphosphoester core was degraded by bacterially produced phosphatase or phospholipase, causing release of the vancomycin and subsequent bacterial destruction. More recently, in a method using adoptive macrophage therapy, Hou et al utilized vitamin lipid nanoparticles to deliver an mRNA strand encoding an AMP-cathepsin B conjugate to cultured macrophages [58]. When delivered to the cytosol of the cell, the mRNA was translated, and the resulting protein conjugate was subsequently trafficked to the lysosome by its cathepsin B tag, where it was cleaved by the enzyme to release the AMP.…”

Addressing Nanomaterial Immunosafety by Evaluating Innate Immunity across Living Species

“…[160] More recently, it was reported that vitamin C lipid NP, used to deliver antimicrobial peptide to macro phage lysosomes, show remarkable antimicrobial activities in fighting multidrug-resistant bacteria, including S. aureus and E. coli, even in immunocompromised septic mice. [161] It should be noted that the vast majority of the results showing little toxic or immunomodulatory effects of NM was obtained in healthy animals or under standard cell culture conditions. The possibility that NM may impact the innate immune defensive mechanisms of weaker, immunocompromised organisms, or under chronic inflammatory conditions is, therefore, still possible and remains under-investigated.…”