Safety Evaluations of Rapamycin Perfluorocarbon Nanoparticles in Ovarian Tumor-Bearing Mice.

Nanomedicine holds great potential for revolutionizing medical treatment. Ongoing research and advancements in nanotechnology are continuously expanding the possibilities, promising significant advancements in healthcare. To fully harness the potential of nanotechnology in medical applications, it is crucial to conduct safety evaluations for the nanomedicines that offer effective benefits in the preclinical stage.

Elucidating allergic reaction mechanisms in response to SARS-CoV-2 mRNA vaccination in adults.

Background: During the COVID-19 pandemic, novel nanoparticle-based mRNA vaccines were developed. A small number of individuals developed allergic reactions to these vaccines although the mechanisms remain undefined.

Methods: To understand COVID-19 vaccine-mediated allergic reactions, we enrolled 19 participants who developed allergic events within 2 h of vaccination and 13 controls, nonreactors.

Systemic delivery of murine SOD2 mRNA to experimental abdominal aortic aneurysm mitigates expansion and rupture.

Background: Oxidative stress is implicated in the pathogenesis and progression of abdominal aortic aneurysm (AAA). Antioxidant delivery as a therapeutic for AAA is of substantial interest although clinical translation of antioxidant therapy has met with significant challenges due to limitations in achieving sufficient antioxidant levels at the site of AAA. We posit that nanoparticle-based approaches hold promise to overcome challenges associated with systemic administration of antioxidants.

Peptide-siRNA nanoparticles targeting NF-κB p50 mitigate experimental abdominal aortic aneurysm progression and rupture.

Abdominal aortic aneurysm (AAA) is a progressive vascular condition associated with high risk of mortality if left untreated. AAA is an inflammatory process with excessive local production of extracellular matrix degrading enzymes, leading to dilatation and rupture of the abdominal aorta. We posit that targeting NF-κB, a signaling pathway that controls inflammation, will halt AAA progression and prevent rupture.

Safety Profile of Rapamycin Perfluorocarbon Nanoparticles for Preventing Cisplatin-Induced Kidney Injury.

Cancer treatment-induced toxicities may restrict maximal effective dosing for treatment and cancer survivors' quality of life. It is critical to develop novel strategies that mitigate treatment-induced toxicity without affecting the efficacy of anti-cancer therapies. Rapamycin is a macrolide with anti-cancer properties, but its clinical application has been hindered, partly by unfavorable bioavailability, pharmacokinetics, and side effects.

Induction of WNT16 via Peptide-mRNA Nanoparticle-Based Delivery Maintains Cartilage Homeostasis.

Osteoarthritis (OA) is a progressive joint disease that causes significant disability and pain and for which there are limited treatment options. We posit that delivery of anabolic factors that protect and maintain cartilage homeostasis will halt or retard OA progression. We employ a peptide-based nanoplatform to deliver Wingless and the name Int-1 (WNT) 16 messenger RNA (mRNA) to human cartilage explants.

Complement activation on neutrophils initiates endothelial adhesion and extravasation.

Neutrophils are essential to the pathogenesis of many inflammatory diseases. In the autoantibody-mediated K/BxN model of inflammatory arthritis, the alternative pathway (AP) of complement and Fc gamma receptors (FcγRs) are required for disease development while the classical pathway is dispensable. The reason for this differential requirement is unknown.

Interleukin-12 and -23 blockade mitigates elastase-induced abdominal aortic aneurysm.

Macrophages play an important role in the inflammatory process that contributes to the development of abdominal aortic aneurysm (AAA). Studies of human and mouse AAA tissue reveal expanded populations of macrophages producing an abundance of pro-inflammatory cytokines, including TNF-α, IL-12p40 and high level of metalloprotease 9 (MMP-9) at the late stages of disease. Herein, we show that blockade of IL-12p40 in the early phase of aneurysm development suppresses macrophage expansion, inflammatory cytokine and MMP-9 production and mitigates AAA development.

Development of a peptide-siRNA nanocomplex targeting NF- κB for efficient cartilage delivery.

Delivery of therapeutic small interfering RNAs (siRNAs) in an effective dose to articular cartilage is very challenging as the cartilage dense extracellular matrix renders the chondrocytes inaccessible, even to intra-articular injections. Herein, we used a self-assembling peptidic nanoparticle (NP) platform featuring a cell penetrating peptide complexed to NF-κB p65 siRNA. We show that it efficiently and deeply penetrated human cartilage to deliver its siRNA cargo up to a depth of at least 700 μm.

Anti-JNK2 peptide-siRNA nanostructures improve plaque endothelium and reduce thrombotic risk in atherosclerotic mice.

Background: A direct and independent role of inflammation in atherothrombosis was recently highlighted by the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial, showing the benefit of inhibiting signaling molecules, eg, interleukins. Accordingly, we sought to devise a flexible platform for preventing the inflammatory drivers at their source to preserve plaque endothelium and mitigate procoagulant risk.

Methods: p5RHH-siRNA nanoparticles were formulated through self-assembly processes.

Contribution of Adipose-Derived Factor D/Adipsin to Complement Alternative Pathway Activation: Lessons from Lipodystrophy.

Factor D (FD) is an essential component of the complement alternative pathway (AP). It is an attractive pharmaceutical target because it is an AP-specific protease circulating in blood. Most components of the complement activation pathways are produced by the liver, but FD is highly expressed by adipose tissue.

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury.

Osteoarthritis (OA) is a major cause of disability and morbidity in the aging population. Joint injury leads to cartilage damage, a known determinant for subsequent development of posttraumatic OA, which accounts for 12% of all OA. Understanding the early molecular and cellular responses postinjury may provide targets for therapeutic interventions that limit articular degeneration.

Neutrophil Extracellular Traps Enhance Early Inflammatory Response in Sendai Virus-Induced Asthma Phenotype.

Paramyxoviral infection in childhood has been linked to a significant increased rate of asthma development. In mice, paramyxoviral infection with the mouse parainfluenza virus type I, Sendai virus (Sev), causes a limited bronchiolitis followed by persistent asthma traits. We have previously shown that the absence of cysteine protease dipeptidyl peptidase I (DPPI) dampened the acute lung inflammatory response and the subsequent asthma phenotype induced by Sev.

Neutrophil Proteases Promote Experimental Abdominal Aortic Aneurysm via Extracellular Trap Release and Plasmacytoid Dendritic Cell Activation.

Objective: We previously established that neutrophil-derived dipeptidyl peptidase I (DPPI) is essential for experimental abdominal aortic aneurysm (AAA) development. Because DPPI activates several neutrophil serine proteases, it remains to be determined whether the AAA-promoting effect of DPPI is mediated by neutrophil serine proteases.

Approach And Results: Using an elastase-induced AAA model, we demonstrate that the absence of 2 neutrophil serine proteases, neutrophil elastase and proteinase-3, recapitulates the AAA-resistant phenotype of DPPI-deficient mice.

Anti-complement activity of the Ixodes scapularis salivary protein Salp20.

Complement, a major component of innate immunity, presents a rapid and robust defense of the intravascular space. While regulatory proteins protect host cells from complement attack, when these measures fail, unrestrained complement activation may trigger self-tissue injury, leading to pathologic conditions. Of the three complement activation pathways, the alternative pathway (AP) in particular has been implicated in numerous disease and injury states.

Quantifying progression and regression of thrombotic risk in experimental atherosclerosis.

Currently, there are no generally applicable noninvasive methods for defining the relationship between atherosclerotic vascular damage and risk of focal thrombosis. Herein, we demonstrate methods to delineate the progression and regression of vascular damage in response to an atherogenic diet by quantifying the in vivo accumulation of semipermeable 200-300 nm perfluorocarbon core nanoparticles (PFC-NP) in ApoE null mouse plaques with [(19)F] magnetic resonance spectroscopy (MRS). Permeability to PFC-NP remained minimal until 12 weeks on diet, then increased rapidly following 12 weeks, but regressed to baseline within 8 weeks after diet normalization.

Anti-mouse properdin TSR 5/6 monoclonal antibodies block complement alternative pathway-dependent pathogenesis.

The complement alternative pathway (AP) is a major contributor to a broad and growing spectrum of diseases that includes age-related macular degeneration, atypical hemolytic uremic syndrome, and preeclampsia. As a result, there is much interest in the therapeutic disruption of AP activity. Properdin, the only positive regulator of the AP, is a particularly promising AP target.

Peptide-siRNA nanocomplexes targeting NF-κB subunit p65 suppress nascent experimental arthritis.

The NF-κB signaling pathway is implicated in various inflammatory diseases, including rheumatoid arthritis (RA); therefore, inhibition of this pathway has the potential to ameliorate an array of inflammatory diseases. Given that NF-κB signaling is critical for many immune cell functions, systemic blockade of this pathway may lead to detrimental side effects. siRNAs coupled with a safe and effective delivery nanoplatform may afford the specificity lacking in systemic administration of small-molecule inhibitors.

Dipeptidyl peptidase I-dependent neutrophil recruitment modulates the inflammatory response to Sendai virus infection.

The role of innate immunity in the pathogenesis of asthma is unclear. Although increased presence of neutrophils is associated with persistent asthma and asthma exacerbations, how neutrophils participate in the pathogenesis of asthma remains controversial. In this study, we show that the absence of dipeptidyl peptidase I (DPPI), a lysosomal cysteine protease found in neutrophils, dampens the acute inflammatory response and the subsequent mucous cell metaplasia that accompanies the asthma phenotype induced by Sendai virus infection.