PROJECT SUMMARY
Sepsis is a complex, heterogenous disease that results in a dysregulated immune response. It is associated
with hyperinflammation, known as “cytokine storm”, causing multiple organ failure and death, as well as
simultaneous compensatory anti-inflammatory responses, leading to immune suppression by abundant anti-
inflammatory cytokine secretion and immune cell death. Sepsis survivors may suffer chronic critical illness,
known as Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PIICS), leading to serious
complications and later death. In sepsis triggered by Gram negative bacterial infection, lipopolysaccharide
(LPS), an endotoxin, promotes uncontrolled inflammation and cytokine storm through TLR4 activation. It can
also trigger significant cell-lytic death of immune cells, known as inflammasome-mediated pyroptosis, which
promotes further immune response for pathogen clearance. However, excessive pyroptosis during
hyperinflammation results in prolonged immunosuppression and increased organ dysfunction, contributing to
the development of PIICS. Currently, there are no available therapies to directly target both excessive cytokine
production and immune cell pyroptosis in sepsis, a gap we will fill with our novel immune modulating itaconate-
loaded telodendrimer nanoparticles (ITA:TD NP). In Luo lab, we have developed a series of bioactive immune
modulating TD nanodrugs, which mimic the molecular pattern of LPS (multivalent charge and fatty acid tails).
As a result, the optimized TD nanodrug attenuates LPS-induced inflammation via competitive binding with
TLR4. Itaconate, a metabolite produced by activated macrophages, is known inhibit immune cell pyroptosis.
Unfortunately, the in vivo application of ITA is limited by the unfavorable pharmacokinetic properties and
cytotoxicity. Our LPS-antagonizing TD nanodrug can form a nanocarrier for efficient encapsulation of itaconate,
thus to synergize the in vivo application and immune modulation. We hypothesize that concurrent inhibition of
LPS signals, inflammasome activation, and membrane pore formation will effectively control both early phase
hyperinflammation and pyroptosis-mediated later stage PIICS for improved sepsis treatment. Preliminary
results indicate a survival benefit with ITA:TD NP treatment in septic mice induced by LPS and effective
inhibition of both inflammation and pyroptosis. Thus, further studies to evaluate ITA:TD NP mechanism of
action and efficacy to prevent both acute and late death in sepsis are needed. The aims of this study are: 1)
investigate ITA:TD NP-mediated inhibition of hyperinflammation in sepsis, and 2) elucidate the protective effect
of ITA:TD NP to prevent PIICS-associated morbidity and mortality. Results from these studies will provide
insight to the mechanism of action of ITA:TD NP and its therapeutic potential for concurrent treatment of
hyperinflammation and prevention of PIICS in sepsis to reduce mortality and fill this critical gap in patient care.
