Group A Streptococcal S Protein Utilizes Red Blood Cells as Immune Camouflage and Is a Critical Determinant for Immune Evasion.

Group A Streptococcus (GAS) is a human-specific pathogen that evades the host immune response through the elaboration of multiple virulence factors. Although many of these factors have been studied, numerous proteins encoded by the GAS genome are of unknown function. Herein, we characterize a biomimetic red blood cell (RBC)-captured protein of unknown function-annotated subsequently as S protein-in GAS pathophysiology. S protein maintains the hydrophobic properties of GAS, and its absence reduces survival in human blood. S protein facilitates GAS coating with lysed RBCs to promote molecular mimicry, which increases virulence in vitro and in vivo. Proteomic profiling reveals that the removal of S protein from GAS alters cellular and extracellular protein landscapes and is accompanied by a decrease in the abundance of several key GAS virulence determinants. In vivo, the absence of S protein results in a striking attenuation of virulence and promotes a robust immune response and immunological memory

Endothelial Dysfunction: Associations with Exposure to Ambient Fine Particles in Diabetic Individuals

BACKGROUND: Exposure to fine airborne particulate matter [<= 2.5 mu m in aerodynamic diameter (PM2.5)] has been associated with cardiovascular and hematologic effects, especially in older people with cardiovascular disease. Some epidemiologic studies suggest that adults with diabetes also may be a particularly susceptible population. OBJECTIVES: The purpose of this study was to analyze the short-term effects of ambient PM2.5 on markers of endothelial function in diabetic volunteers.METHODS: We conducted a prospective panel study in 22 people with type 2 diabetes mellitus in Chapel Hill, North Carolina (USA), from November 2004 to December 2005. We acquired daily measurements of PM2.5 and meteorologic data at central monitoring sites. On 4 consecutive days, we measured endothelial function by brachial artery ultrasound in all participants and by pulsewave measurements in a subgroup. Data were analyzed using additive mixed models with a random participant effect and adjusted for season, day of the week, and meteorology. RESULTS: Flow-mediated dilatation decreased in association with PM2.5 during the first 24 hr, whereas small-artery elasticity index decreased with a delay of 1 and 3 days. These PM2.5-associated decrements in endothelial function were greater among participants with a high body mass index, high glycosylated hemoglobin Ale, low adiponectin, or the null polymorphism of glutathione S-transferase M1. However, high levels of myeloperoxidase on the examination day led to strongest effects on endothelial dysfunction. CONCLUSIONS: These data demonstrate that PM2.5 exposure may cause immediate endothelial dysfunction. Clinical characteristics associated with insulin resistance were associated with enhanced effects of PM on endothelial function. In addition, participants with greater oxidative potential seem to be more susceptible

Biomimetic Nanocarriers to Address Bacterial Infections and Inflammation

Biomimetic technology takes cues from nature’s elegant engineering and applies these principles to novel therapeutics. By endowing nanoparticle and microparticle scaffolds with complex, multivalent functionalities, biomimicry allows us to enhance the potency of drug molecules and vaccines without sacrificing patient safety. In particular, membrane coated nanoparticles, derived from native extracellular and cellular membranes present in nature, have demonstrated tremendous success treating and protecting against various diseases. The first chapter of this dissertation explores biomimicry and its applications in nanomedicine in the context of bacteria. The remaining chapters of this dissertation apply these design principles to disease states. Through novel biomimetic designs, dosage requirements for effective treatment and vaccination are significantly reduced. Chapter two focuses on the design, fabrication, and application of extracellular membrane coated nanoparticles to treat lung disease. By endowing anti-inflammatory nanoparticulate cores with lung-tropic breast cancer exosome membrane, lung inflammation can be successfully managed with a lower therapeutic dose. The third chapter of this dissertation is dedicated to biomimetic vaccination against anthrax utilizing a known anthrax virulence mechanism. Macrophage membrane cloaked nanoparticles containing a potent adjuvant are further functionalized with an anthrax toxin to enable antigen-adjuvant co-delivery and single, low-dose vaccine protection. Overall, the rational design principles presented in this dissertation serve as a framework to develop a wide range of highly efficient, low-dose biomimetic nanocarriers to address unmet clinical needs

Biomimetic Nanotechnology toward Personalized Vaccines

While traditional approaches for disease management in the era of modern medicine have saved countless lives and enhanced patient well-being, it is clear that there is significant room to improve upon the current status quo. For infectious diseases, the steady rise of antibiotic resistance has resulted in super pathogens that do not respond to most approved drugs. In the field of cancer treatment, the idea of a cure-all silver bullet has long been abandoned. As a result of the challenges facing current treatment and prevention paradigms in the clinic, there is an increasing push for personalized therapeutics, where plans for medical care are established on a patient-by-patient basis. Along these lines, vaccines, both against bacteria and tumors, are a clinical modality that could benefit significantly from personalization. Effective vaccination strategies could help to address many challenging disease conditions, but current vaccines are limited by factors such as a lack of potency and antigenic breadth. Recently, researchers have turned toward the use of biomimetic nanotechnology as a means of addressing these hurdles. Recent progress in the development of biomimetic nanovaccines for antibacterial and anticancer applications is discussed, with an emphasis on their potential for personalized medicine

Biomimetic nanoparticle technology for cardiovascular disease detection and treatment

Cardiovascular disease (CVD), which encompasses a number of conditions that can affect the heart and blood vessels, presents a major challenge for modern-day healthcare. Nearly one in three people has some form of CVD, with many suffering from multiple or intertwined conditions that can ultimately lead to traumatic events such as a heart attack or stroke. While the knowledge obtained in the past century regarding the cardiovascular system has paved the way for the development of life-prolonging drugs and treatment modalities, CVD remains one of the leading causes of death in developed countries. More recently, researchers have explored the application of nanotechnology to improve upon current clinical paradigms for the management of CVD. Nanoscale delivery systems have many advantages, including the ability to target diseased sites, improve drug bioavailability, and carry various functional payloads. In this review, we cover the different ways in which nanoparticle technology can be applied towards CVD diagnostics and treatments. The development of novel biomimetic platforms with enhanced functionalities is discussed in detail

Nanoparticle Delivery of Immunostimulatory Agents for Cancer Immunotherapy.

Immunostimulatory agents, including adjuvants, cytokines, and monoclonal antibodies, hold great potential for the treatment of cancer. However, their direct administration often results in suboptimal pharmacokinetics, vulnerability to biodegradation, and compromised targeting. More recently, encapsulation into biocompatible nanoparticulate carriers has become an emerging strategy for improving the delivery of these immunotherapeutic agents. Such approaches can address many of the challenges facing current treatment modalities by endowing additional protection and significantly elevating the bioavailability of the encapsulated payloads. To further improve the delivery efficiency and subsequent immune responses associated with current nanoscale approaches, biomimetic modifications and materials have been employed to create delivery platforms with enhanced functionalities. By leveraging nature-inspired design principles, these biomimetic nanodelivery vehicles have the potential to alter the current clinical landscape of cancer immunotherapy

Bacteria-Inspired Nanomedicine

The natural world has provided a host of materials and inspiration for the field of nanomedicine. By taking design cues from naturally occurring systems, the nanoengineering of advanced biomimetic platforms has significantly accelerated over the past decade. In particular, the biomimicry of bacteria, with their motility, taxis, immunomodulation, and overall dynamic host interactions, has elicited substantial interest and opened up exciting avenues of research. More recently, advancements in genetic engineering have given way to more complex and elegant systems with tunable control characteristics. Furthermore, bacterial derivatives such as membrane ghosts, extracellular vesicles, spores, and toxins have proven advantageous for use in nanotherapeutic applications, as they preserve many of the features from the original bacteria while also offering distinct advantages. Overall, bacteria-inspired nanomedicines can be employed in a range of therapeutic settings, from payload delivery to immunotherapy, and have proven successful in combatting both cancer and infectious disease

Virus‐Mimicking Cell Membrane‐Coated Nanoparticles for Cytosolic Delivery of mRNA

Effective endosomal escape after cellular uptake represents a major challenge in the field of nanodelivery, as the majority of drug payloads must localize to subcellular compartments other than the endosomes in order to exert activity. In nature, viruses can readily deliver their genetic material to the cytosol of host cells by triggering membrane fusion after endocytosis. For the influenza A virus, the hemagglutinin (HA) protein found on its surface fuses the viral envelope with the surrounding membrane at endosomal pH values. Biomimetic nanoparticles capable of endosomal escape were fabricated using a membrane coating derived from cells engineered to express HA on their surface. When evaluated in vitro, these virus-mimicking nanoparticles were able to deliver an mRNA payload to the cytosolic compartment of target cells, resulting in the successful expression of the encoded protein. When the mRNA-loaded nanoparticles were administered in vivo, protein expression levels were significantly increased in both local and systemic delivery scenarios. We therefore conclude that utilizing genetic engineering approaches to express viral fusion proteins on the surface of cell membrane-coated nanoparticles is a viable strategy for modulating the intracellular localization of encapsulated cargoes