Marcos-Contreras, O. A. | Search bioRxiv

bioRxiv2022

Targeted nanocarriers coopting pulmonary leukocytes for drug delivery to the injured brain

Selective drug delivery to injured regions of the brain is an elusive, but biomedically important, goal. It is tempting to co-opt migrating white blood cells (WBC) to carry drugs to the injured brain, using natural WBC tropism. Current approaches to load cargoes to WBC have limited utility, particularly in acute conditions, due to the need for time consuming ex vivo manipulation and loading of cells. Physiological, in vivo loading of WBC may be advantageous in this scenario. Here we devised such a strategy, capitalizing on the unique features of the direct blood exchange between brain and lungs. Mediators emanating from the injured brain directly travel to the pulmonary vasculature via venous flow. In response to these mediators, WBCs, transiently residing in the pulmonary microvascular lumen, disembark and flow with arterial blood to the brain microvasculature, where they adhere and transmigrate to the brain parenchyma via the local chemoattractant gradient. We posited that direct in vivo targeting of cargoes to the pulmonary WBC pool may provide drug transfer to brain via this natural mechanism. To test this, we intravenously injected agents targeted to intercellular adhesion molecule 1 (ICAM) in mice with acute brain inflammation caused by direct injection of tumor necrosis factor alpha (TNF-). We found that: A) At 2 hours, >20% of ICAM/NP accumulated in lungs, predominantly in WBCs; B) At 6 and 22 hours, ICAM/NP pulmonary uptake markedly decreased; C) In contrast, ICAM/NP uptake in brain increased ~5-fold in this time interval, concomitantly with migration of WBCs to the brain. Cranial window fluorescent microscopy confirmed WBC transport of ICAM/NP to the brain in TNF--challenged mice beyond the BBB. Importantly, demonstrating the pharmacologic relevance of this strategy, dexamethasone-loaded ICAM/liposomes abrogated brain edema in this model. In sum, coopting the natural homing of WBC from the lungs via ICAM-targeting to injured brain is an attractive strategy for precise interventions for treatment of acute brain injuries. VISUAL ABSTRACT O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

pharmacology and toxicology↗

bioRxiv2020

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

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.

bioengineering↗