The mechanism and the immunomodulatory consequences of protein adsorption on stealth nanoparticles (B08#)

• Subject Area: Structural Biology ; Biophysics ; Immunology ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 316213987

Despite the successful use of nanoparticles in various medical applications, the molecular basis of nanoparticle / host interactions in inflammatory diseases needs to be established. Controlling and beneficially engineering the interactions that determine the cellular fate and the organismic (patho)physiological responses is of fundamental interest for the medical application of nanoparticles. Polymer-based nanoparticles with“stealth” properties were developed to avoid undesired interactions with immunecompetent cells. However, the behavior of these nanoparticles in the altered serum conditions found in patients fighting systemic infections such as sepsis remains poorly studied, in particular regarding the molecular mechanisms of biomolecular interactions, cellular uptake, distribution, and immunomodulatory effects of nanoparticles.Sepsis is a severe medical condition threatening millions of lives every year. One of the most important clinical markers for inflammation and infection is C-reactive protein (CRP), whose serum levels can rise >100-fold during infection. High serum levels of CRP are correlated with a poor prognosis in sepsis. Based on our preliminary data where we show that CRP readily interacts with nanoparticles giving rise to different immunemodulatory properties, CRP represents a prime candidate to study the molecular details of protein-polymer-based nanoparticle interaction and the downstream consequences, e.g. targeting and cellular responses. Importantly, both full-length CRP and peptides corresponding to its intrinsically disordered regions (IDRs) can have either pro- or anti-inflammatory effects. IDRs are prone to conformational rearrangements upon surface interaction and could, therefore, be responsible for distinct inflammatory responses to nanoparticle-bound CRP. While structural disorder is prevalent in >40% of the human proteome and intrinsically disordered proteins (IDPs) are remarkably versatile biomolecular interaction partners, the effects of (dis)order on protein interactions with (stealth) nanoparticles in general is largely unknown.Here, we will investigate the molecular interactions between poly(lactic-co-glycolic acid) (PLGA)-based stealth nanoparticles modified with poly(ethylene glycol) (PEG) or poly(2-ethyl-2-oxazoline) (POx) and selected proteins including CRP to establish structure-property relationships. By systematically varying the nanoparticle (e.g. PLGA- and stealth polymer molar mass) as well as the protein (structured, intrinsically disordered) properties, we aim to identify general as well as nanoparticle- and proteinspecific structural and physicochemical features governing the interaction of proteins with PEG/POx-based nanoparticles. The influence of the varying properties of these stealth nanoparticles on the molecular responses of immune cells during health and inflammation will be studied in vitro and in vivo.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1278: Polymer-based nanoparticle libraries for targeted anti-inflammatory strategies
• Applicant Institution: Friedrich-Schiller-Universität Jena
• Project Heads: Professorin Dr. Ute Hellmich, since 7/2022; Professor Dr. Adrian Press, since 7/2022