PEG & ADC

Cell therapy of vitamin-lipid nanoparticles to treat sepsis

Sepsis is an organ dysfunction caused by the host’s abnormal immune response to infection. Sepsis affects millions of people worldwide every year and is one of the leading causes of death in hospitals. Due to the bacterial resistance problems, it is more difficult to treat sepsis caused by drug-resistant bacterial infections.

Sepsis has been considered an uncontrollable inflammatory response of the host to infection. However, recent clinical data indicate that most patient’s immune responses will from a transient activation state to a long-term inhibitory. The immunosuppression by the inactivation or death of immune cells can hinder the body’s elimination of infection. Besides, it enhances the patient’s sensitivity to nosocomial infections and ultimately weakens the treatment effect of sepsis.

Macrophage is one of the main participants in host immune defense. For a patient with immunosuppressive symptoms, Inactivated macrophages are one of the main reasons unable to clear the infection. Some small clinical trials have shown, restoring the inactivated macrophage’s function by immunostimulatory drugs can enhance the ability to clear infections. However, it did not significantly improve the patient’s survival rate. The reasons may be:

(1)Immunostimulatory drugs cannot fully restore the function of inactivated macrophages;

(2)Macrophages mainly wrap bacteria in their phagolysosome and pass active nitrogen oxides and lysosomal enzymes to kill germs. Many bacteria can achieve intracellular survival by resisting these bactericidal mechanisms and eventually lead to infection and recurrences. Such as Staphylococcus aureus and Escherichia coli.

(3)Despite antibiotic therapy is one of the basic clinical treatments for bacterial sepsis, 70-80% of sepsis deaths still persistent infections. It may be the lack of effective antibacterial drugs against some resistant bacteria.

On January 6, 2020, the research group of Dong Yizhou of the Ohio State University School of Pharmacy published an article “Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis” in Nature Nanotechnology. This research work integrates vitamin C-derived nanotechnology and cell therapy, which greatly improves the survival rate of septic animals.

In this study, someone speculates that if the lysosomes of macrophages contain exogenous antimicrobial peptides, and are transferred to a host with immunosuppressive symptoms, the above problems may be solved.

Firstly, normal macrophages can replace inactivated macrophages to achieve bacterial clearance. And avoid the problem that immune-stimulating drugs cannot fully restore the function of macrophages.

Secondly, the bacteria can resist the phagolysosome’s related bactericidal mechanism, but exogenous antimicrobial peptides can enhance the phagolysosome’s bactericidal activity. Then to avoid the immune escape of the bacteria.

Finally, the antimicrobial peptide is effective against a variety of drug-resistant bacteria, so it helps to clear drug-resistant bacterial infections.

To test this hypothesis, someone designed and constructed messenger ribonucleic acid. For it efficiently deliver the mRNA into macrophages, and synthesized a series of vitamin-lipid compounds(Vitamin-Lipids). Through screening and orthogonal optimization, then obtained the optimal composition based on vitamin C lipid nanoparticles(VcLNPs).

As shown in the figure, after vitamin C nanoparticles enter macrophages, mRNA is released into the cytoplasm. It can translate into antimicrobial peptide-enzyme sensitive peptide-lysosomal signal protein tri-block protein. Under the guidance of the lysosomal signal protein, the triblock protein enters the lysosome, and the enzyme-sensitive peptide is cleaved by the lysosomal enzyme, and the antibacterial peptide is released into the lysosome.

When the macrophage comes into contact with the bacteria, the bacteria are first encapsulated in the phagosome, and then the phagosome fuses with the lysosome to form a phagolysosome. At this time, the exogenous antimicrobial peptides and other bactericidal components in the lysosome are dissolved together In the phagosome, a synergistic bactericidal effect is achieved.

In a murine sepsis model, this cell therapy method effectively reduces the number of drug-resistant bacteria in the body, improves the physical function of the host, and the survival rate of the sepsis host induced by drug-resistant bacteria.

It is reported that the study is currently in the preclinical research stage. Researchers are working closely with clinicians, hoping that the technology can help patients with drug-resistant bacterial infections and sepsis.

Reference

nature.com/articles/s41565-019-0600-1