Multimodal Nanoparticles for Severe Inflammation and Sepsis

Summary Sepsis is a life-threatening, multifaceted condition that develops due to an uncontrolled host immune response to an infection. A 2017 study reported an estimated 48.9 million incident cases of sepsis worldwide with total sepsis-related deaths representing nearly 20% of all global deaths. It has been hypothesized that the clinical heterogeneity and different sepsis endotypes, treatment modalities targeted only towards a single molecular pathway, and timing of therapeutic intervention are major contributors to the poor clinical results. Survivors generally suffer from additional morbidities for years, including higher risk of readmission, cardiovascular disease, and cognitive impairment, due to the development of trained immunity and a state of immune suppression. Our long-term goal is to develop a simple and broad-acting nanoparticle (NP)-based immunotherapy to address the complex and multifaceted immune dysregulation in sepsis. Towards this goal, we developed immunomodulatory nanoparticles (iNPs) – a ‘drug-free’ class of poly(lactic acid) (PLA)-based NPs to augment multiple aspects of innate immunity and promote sepsis survival. The objectives of this MPI R01 proposal are built upon several foundational findings by our team. First, intraperitoneal administration of iNPs significantly improved survival in two representative mouse models of sepsis, namely, lipopolysaccharide (LPS)-induced endotoxemia (sterile inflammation) and cecal ligation and puncture (CLP) (polymicrobial sepsis) when applied as an adjuvant to an antibiotic regimen. Second, iNPs utilize a multimodal mechanism of action that leverages both physical (nanoformulation) and compositional (lactic acid) features to reduce Toll-like receptor (TLR) agonist-macrophage interactions and proinflammatory responses, increase innate immune cell survival, and inhibit inflammatory signaling pathways. Third, iNP treatment retained the population of large peritoneal macrophages (LPMs) in vivo, a critical cell type required for sepsis survival. Herein, we propose a rigorous R01 research project to: 1) evaluate the inherent immunomodulatory properties of a focused set of iNPs to achieve maximal therapeutic efficacy in the CLP sepsis model; 2) identify the cellular and molecular mechanisms underlying iNP effects; and 3) determine the therapeutic window for safe and effective iNP treatment. In Aim 1, we will investigate how select physicochemical properties of iNPs contribute to modulated inflammatory responses, and bacterial clearance, while comprehensively investigating their in vitro and in vivo cellular and molecular mechanisms to treat sepsis. In Aim 2, we will establish the therapeutic window for iNP administration. Timing and dosing effects related to iNP efficacy and organ function will be determined and iNPs will be assessed using distinct, clinically relevant scenarios reflective of suspected and early onset of sepsis. If successful, our work is anticipated to identify a novel and readily translatable, NP-based immunotherapeutic solution to improve patient outcomes in sepsis.