Designer Artificial Cells: Customized Cell Membrane-Coated Porous Nanoparticles for Targeting Lethal Cytokine Storm

Background: Cytokine storm is induced by immune overactivation in response to an infection or an injury. Although not understood well, cytokine storm is considered as a major cause of mortality in the 1918-20 "Spanish flu," and the current COVID-19 pandemic. Cytokine storm can also be triggered by exposure toxic smoke or chemical fume, which are common triggers for military personnel. If unmanaged, cytokine storm results in acute respiratory distress syndrome (ARDS). Current management for ARDS focuses on symptom releasing including oxygenation and ventilation. Similarly, therapies for treating viral infections aim to eliminate the viruses, whereas in acute cases of cytokine storm and ARDS, clearance of excess immune cytokines and calming the immune overactivation is the primary goal. Rationale: Current challenge in the cell membrane-coated nanoparticles (CMCNPs) field is the low biocompatibility and immunogenicity of CMCNPs for direct deliver in patients. To overcome these challenges, this project endeavors to develop Designer Artificial Cells (DAC) for neutralizing cytokine storm and controlling immune overactivation. Hypothesis: Under natural conditions, the body manages cytokine storms by binding cytokines to cell surface receptor that render them inactive and releasing anti-inflammatory signaling molecules. This proposal hypothesizes that a biomimicking system, which can emulates these two functions of the immune system, has the potential to neutralize cytokine storm and dampen severe inflammatory immune response. The DAC hold the potential as a non-immunogenic nanomedicine platform that mimic both of these functions of the immune cells. Study Design: Firstly, the fabrication of DAC with tuneable cytokine suppression function and will be synthesized, optimized, and characterized in vitro. Transmembrane receptor binding stability and payload release from the pSiNP will be assessed. Then, the neutralizing efficacy, its immunogenicity and stability in suppressing immune activation will be assess in vitro using inflammatory human macrophages. Finally, to determine the in vivo efficacy, DAC will be tested in a humanized mouse model with cytokine storm induced by influenza virus A infection. Innovation: Key innovations of the project are; 1) tunable and customizable cell membrane coatings embedded with required amount of desired transmembrane cytokine receptor; 2) ability to load and release immune suppressive drugs from the porous nanoparticle core; 3) fabrication using off-the-shelf components with no chances for immunogenic response (i.e., the cell membrane coating in the DAC is composed of O type human red blood cells bilipid membrane (RBCM) embedded with commercially available transmembrane receptor). These innovative aspects of this project will allow for rapid clinical translation of the DAC. Outcomes of the project will develop a platform technology that can be easily modified and tuned for treating cytokine storms induced by a variety of triggers including pathogens and toxins, etc. This platform will also aid future generations of drug development and drug delivery. Less