Friday, March 14, 2025
3/14/2025
Abstract The overwhelming immune response to systemic infection and traumatic injury may result in hyperinflammation, multiple organ failure, and death in sepsis. Sepsis is a complex and heterogeneous critical illness with multiple dynamic dysregulated inflammatory pathways triggered by systemically released Damage or Pathogen Associated Molecular Patterns (DAMPs/PAMPs). Dysregulated inflammation also contributes to the pathogenesis of many other diseases, e.g. autoimmune diseases, chronic wounds, etc. Clinical challenges: Versatile immune modulation therapy to resolve inflammation in critical illness is still a significant unmet need. Therapeutics targeting a specific inflammatory mediator, e.g. cytokines or DAMPs/PAMPs, have failed to improve sepsis survival in the clinic. On the contrary, anti-inflammatory steroid drugs are associated with immune suppression, resulting in an increased risk of secondary infections. Solutions: I have developed a novel, well-defined linear-dendritic telodendrimer (TD) nanoplatform for structure-based nanocarrier design in therapeutic delivery and immune modulation. In my on-going R01 project, I have developed TD nanotrap (NT) platforms for both systemic injection and hemoperfusion therapy to passively capture a broad spectrum of the overflowing inflammatory signals simultaneously, e.g. LPS, cytokines, and DAMPs/PAMPs, to restore immune regulation. The optimized TD NT resins provide a cure in a severe sepsis mouse model when combined with a moderate dose of antibiotics, as reported in our recent publications in Nature Communications 2020 and Advanced Therapeutics 2022. Recently, we created a series of novel TD constructs with a well-defined and optimal combination of negative charges and hydrophobic moieties that can actively block immune cell inflammation triggered by various immune stimulating molecules, e.g. endotoxins from gram negative bacteria (LPS) and gram positive bacteria (LTA), as well as bacterial cell lysate and even TNF-α. At the same time, these TDs can assemble into nanocarriers for the encapsulation of vital antibiotics for infection control; they can also effectively deliver endogenous potent pyroptosis inhibitors to control hyperinflammation and prevent immune suppression in the later stage of sepsis. In the next five years, I will focus on the development of transformative, next generation multimodal TD nanodrugs for sepsis treatment in three directions: PROJECT- 1: Develop a novel next-generation bioactive TD nanodrug for inflammation control; PROJECT-2: Develop multi-functional TD nanotherapeutics to inhibit pyroptosis in sepsis; PROJECT-3: Develop multimodal TD nanomedicine to control infection and inflammation in sepsis. In addition to sepsis, these TD nanodrugs can also be applied in other inflammatory diseases, e.g., ARDS, chronic wounds, cancer perioperative inflammation, rheumatoid arthritis, and inflammatory bowel diseases, etc. In summary, our innovative TD nanodrugs are poised to provide resolution to inflammation and improve sepsis survival in the clinic by both immune modulation and infection control.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).