Supramolecular Organization Predicts Protein Nanoparticle Delivery to Neutrophils for Acute Lung Inflammation Diagnosis and Treatment

Abstract

Acute lung inflammation has severe morbidity, as seen in COVID-19 patients. Lung inflammation is accompanied or led by massive accumulation of neutrophils in pulmonary capillaries ("margination"). We sought to identify nanostructural properties that predispose nanoparticles to accumulate in pulmonary marginated neutrophils, and therefore to target severely inflamed lungs. We designed a library of nanoparticles and conducted an in vivo screen of biodistributions in naive mice and mice treated with lipopolysaccharides. We found that supramolecular organization of protein in nanoparticles predicts uptake in inflamed lungs. Specifically, nanoparticles with agglutinated protein (NAPs) efficiently home to pulmonary neutrophils, while protein nanoparticles with symmetric structure (e.g. viral capsids) are ignored by pulmonary neutrophils. We validated this finding by engineering protein-conjugated liposomes that recapitulate NAP targeting to neutrophils in inflamed lungs. We show that NAPs can diagnose acute lung injury in SPECT imaging and that NAP-like liposomes can mitigate neutrophil extravasation and pulmonary edema arising in lung inflammation. Finally, we demonstrate that ischemic ex vivo human lungs selectively take up NAPs, illustrating translational potential. This work demonstrates that structure-dependent interactions with neutrophils can dramatically alter the biodistribution of nanoparticles, and NAPs have significant potential in detecting and treating respiratory conditions arising from injury or infections.

Biomaterial-based immunoengineering to fight COVID-19 and infectious diseases

“…To mitigate acute inflammation, activated neutrophils can be selectively targeted with nanoparticles containing agglutinated 105 or denatured proteins, 106 which bind to Fcg RIII receptors on activated neutrophils. 107 The feasibility of this approach is demonstrated with nanoparticles made from denatured albumin loaded with an anti-inflammatory drug, which are preferentially internalized by activated neutrophils.…”

The Nano-War Against Complement Proteins

“…While most nanoengineering will continue to focus on avoiding the deleterious aspects of complement, we recently found that complement opsonization can also be utilized to create a therapy. We screened a large array of nanomaterials for uptake into the lungs of mice that had received nebulized lipopolysaccharide (LPS), a model of acute respiratory distress syndrome (ARDS), the lung inflammation that kills in COVID-19 [37]. We found that nanoparticles with agglutinated surface protein (NAPs; e.g., albumin nanoparticles), but not nanoparticles with near-crystalline arrangement of surface proteins (e.g., ferritin nanocages), had a strong tropism for marginated neutrophils in the lungs of the LPS mice.…”

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

“…Recent work has shown that asymmetric lysozyme-dextran nanogels and cross-linked albumin nanoparticles with agglutinated proteins in amorphous nanostructures particularly target neutrophils during lung injury as demonstrated both in vivo in mice and also using human lungs, which could be critically valuable for selective treatment and/or distraction of neutrophils during COVID-19. 295 These examples demonstrate that inflammation can be reduced and innate immune cells can be redirected from the sites of injury, which could be very valuable for the therapeutic treatment of COVID-19, especially in light of increased neutrophil-lymphocyte ratios found in 80% of patients infected with SARS-CoV-2. 102 These distraction methods can also potentially be used in tandem with previously discussed drug delivery approaches, leveraging vascular targeting.…”