Nanotherapy to modulate the immune response in sepsis – NANOSEPSIS

Sepsis is a leading global cause of death that is linked to the dysregulated systemic inflammatory response to an infection. The innate immune response to foreign bacterial molecules typically induces the activation of circulating monocytes and the production of pro-inflammatory cytokines. This signal cascade stimulates the recruitment of immune cells to fight the infection. However, during sepsis, the presence of foreign pathogens in the blood induces an inappropriate massive systemic activation of the immune system that can cause hypotension, multiple organ failure and death.

Unfortunately, other than antibiotic regimens in combination with cardiovascular/respiratory supports, there is no established cure for sepsis, leading to a mortality rate up to 50% in case of septic shock and causing, based on WHO estimates, 6 million deaths annually. The main hurdle encountered in the development of immunomodulatory treatments for sepsis is the coexistence of a hyper-inflammation reaction and a hypo-inflammation phase. Indeed, clinicians agree that while traditional anti-inflammatory therapies can reduce early mortality in sepsis, their non-targeted effects can exacerbate the immunosuppressive phase and increase late mortality. Based on this paradigm, we believe that to be effective, anti-inflammatory therapeutic strategies in sepsis need to feature two key characteristics: a rapid effect and a high selectivity toward systemic inflammation to protect the integrity of immune system needed to fight the infection.

In this application, we propose to develop and test a library of new nanoparticles with a high affinity toward blood inflammatory monocytes. Those cells were chosen as target as they are not only the first cellular mediator of sepsis systemic inflammation, but also because they are readily accessible within the blood circulation to nanoparticles administered intravenously. These nanoparticles will then be loaded with a novel highly specific inhibitor that has demonstrated anti-inflammatory activity targeted toward inflammatory monocytes without harming the host immune system.

The first part of our project will be to develop a series of nanoparticles of different chemical compositions in order to obtain the best formulations in terms of size, loading efficiency and stability. The most promising formulations will then be tested in different cell models to measure their targeting specificity toward pro-inflammatory monocytes as well as their anti-inflammatory effect. The best nanoparticles will finally be tested in different mouse models of sepsis to investigate their biodistribution, pharmacokinetics and therapeutic efficacy.

We believe that thanks to our unique combination of cellular addressing (nanoparticles) and molecular selectivity (specific inhibitor), our strategy will enable the reduction of the inflammatory component of sepsis without weakening the immune system.