Biomaterials-Based Opportunities to Engineer the Pulmonary Host Immune Response in COVID-19

Abstract

The COVID-19 pandemic caused by the global spread of the SARS-CoV-2 virus has led to a staggering number of deaths worldwide and significantly increased burden on healthcare as nations scramble to find mitigation strategies. While significant progress has been made in COVID-19 diagnostics and therapeutics, effective prevention and treatment options remain scarce. Because of the potential for the SARS-CoV-2 infections to cause systemic inflammation and multiple organ failure, it is imperative for the scientific community to evaluate therapeutic options aimed at modulating the causative host immune responses to prevent subsequent systemic complications. Harnessing decades of expertise in the use of natural and synthetic materials for biomedical applications, the biomaterials community has the potential to play an especially instrumental role in developing new strategies or repurposing existing tools to prevent or treat complications resulting from the COVID-19 pathology. Leveraging microparticle- and nanoparticle-based technology, especially in pulmonary delivery, biomaterials have demonstrated the ability to effectively modulate inflammation and may be well-suited for resolving SARS-CoV-2-induced effects. Here, we provide an overview of the SARS-CoV-2 virus infection and highlight current understanding of the host's pulmonary immune response and its contributions to disease severity and systemic inflammation. Comparing to frontline COVID-19 therapeutic options, we highlight the most significant untapped opportunities in immune engineering of the host response using biomaterials and particle technology, which have the potential to improve outcomes for COVID-19 patients, and identify areas needed for future investigations. We hope that this work will prompt preclinical and clinical investigations of promising biomaterials-based treatments to introduce new options for COVID-19 patients.

Keywords: COVID-19; SARS-CoV-2; biomaterials; immune engineering; inflammation; nanoparticles.

Figure 1.. Immune landscape of the alveolar region in healthy, mild, and severe states during COVID-19.

A) Infection of type II alveolar epithelial cells with SARS-CoV-2 through the ACE2 receptor B) Activation of alveolar macrophages following infection/recognition of virus and release of pro-inflammatory cytokines C) Type I IFN response initiated by plasmatocytoid dendritic cells (pDCs) and recruitment of lymphocytes D) Plasma B cells producing SARS-CoV-2-specific antibodies following maturation and priming by innate immune cells E) SARS-CoV-2-specific CD8+ T cells causing apoptosis of infected cells F) Impaired type I IFN response G) Cytokine storm by activated macrophages and recruited inflammatory leukocytes H) Deposition of fibrous strands and extracellular matrix leading to fibrosis and scarring I) Degranulation of activated neutrophils recruited from the bloodstream J) Fluid buildup in the alveolus from edemous tissue and widening of interstisium K) Shedding of ciliated epithelial lining and formation of debris.

Figure 2.. Potential particle engineering features for host immune modulation in COVID-19.

A) Tailorability of design and building blocks to accommodate a wide range of applications and cargo loading and ensure biocompatibility. B) Modular surface design with functional ligands and receptors that are capable of interacting with high specificity with lung immune cells or proteins. C) Controlled degradation and cargo release in low pH environments upon internalization by lung phagocytes. D) Tunability of nanomaterial properties for optimal deposition in the airways and targeting through vasculature.

Figure 3:. Summary of potential particle-based pulmonary immune engineering approaches for COVID-19.

A) Engineering nanoparticle vaccines for enhanced association with migratory dendritic cells and increased lymph node trafficking to prime adaptive immunity. B) Nanoparticles as viral decoys displaying ACE2 to bind SARS-CoV-2 and inhibit infection of alveolar cells. C) Nanoparticles with functional ligands to sequester pro-inflammatory cytokines and prevent cytokine storm. D) Use of nanoparticles and loaded cargo to drive polarization of inflammatory M1 macrophages towards anti-inflammatory M2 macrophages. E) Phagocyte distraction with injected nanoparticles.