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

Biomimetic Nanoparticles for Targeted Delivery and Removal

Nanoparticle drug delivery has revolutionized the way we think of disease treatment over the last decade. The encapsulation of drugs into nanoparticles has led to better bioavailability, longer circulation times and an extended therapeutic window, and fewer off target effects than free drug administration. Nanoparticles are able to be tailored to specific applications through their size, shape, and surface design. Nanoparticles are just beginning to see clinical translation and FDA approval. Recently, significant efforts have been put into creating biomimetic targeting, particularly utilizing cell membrane coatings. Cell membrane can be used as a biomaterial to “cloak” nanoparticles, endowing them with the surface properties of the parent cell. Each different cell type in the body has a distinct surface structure with lipids, proteins, and receptors perfectly tailored to its purpose and location. Some of these proteins, such as CD47 or the selectins, have well known purposes like immune evasion or specific receptor targeting respectively. Additionally, there are yetundescribed and uncharacterized surface moieties on cells whose properties can be retained by using the entire cell membrane as a biomaterial. By cloaking nanoparticles in cell membrane, they retain many of the properties of the original cell type. We show that this allows for new biointerfacing abilities and a highly specific drug delivery vehicle. This new technology also promises future clinical translation,as the materials are inherently biocompatible. Herein, we will discuss engineered nanoparticle platforms that utilize this biomimetic cell membrane coating technology to improve the delivery of drugs, and additionally the detoxification and removal of pathogens. The biomimetic techniques developed during this PhD range from novel formulations of classical small molecule targeting for cancer therapy, to new methods of utilizing a fusion of natural cell membranes to create custom tailored targeting. These improvements to the field of targeted drug delivery will hopefully lead to better use of drugs and treatment of disease, and a higher level of tailoring ability available to engineers designing future platforms

Biomimetic Nanoparticles for Targeted Delivery and Removal

Nanoparticle drug delivery has revolutionized the way we think of disease treatment over the last decade. The encapsulation of drugs into nanoparticles has led to better bioavailability, longer circulation times and an extended therapeutic window, and fewer off target effects than free drug administration. Nanoparticles are able to be tailored to specific applications through their size, shape, and surface design. Nanoparticles are just beginning to see clinical translation and FDA approval. Recently, significant efforts have been put into creating biomimetic targeting, particularly utilizing cell membrane coatings. Cell membrane can be used as a biomaterial to “cloak” nanoparticles, endowing them with the surface properties of the parent cell. Each different cell type in the body has a distinct surface structure with lipids, proteins, and receptors perfectly tailored to its purpose and location. Some of these proteins, such as CD47 or the selectins, have well known purposes like immune evasion or specific receptor targeting respectively. Additionally, there are yetundescribed and uncharacterized surface moieties on cells whose properties can be retained by using the entire cell membrane as a biomaterial. By cloaking nanoparticles in cell membrane, they retain many of the properties of the original cell type. We show that this allows for new biointerfacing abilities and a highly specific drug delivery vehicle. This new technology also promises future clinical translation,as the materials are inherently biocompatible. Herein, we will discuss engineered nanoparticle platforms that utilize this biomimetic cell membrane coating technology to improve the delivery of drugs, and additionally the detoxification and removal of pathogens. The biomimetic techniques developed during this PhD range from novel formulations of classical small molecule targeting for cancer therapy, to new methods of utilizing a fusion of natural cell membranes to create custom tailored targeting. These improvements to the field of targeted drug delivery will hopefully lead to better use of drugs and treatment of disease, and a higher level of tailoring ability available to engineers designing future platforms

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

Erythrocyte membrane-cloaked polymeric nanoparticles for controlled drug loading and release.

AimPolymeric nanoparticles (NPs) cloaked by red blood cell membrane (RBCm) confer the combined advantage of both long circulation lifetime and controlled drug release. The authors carried out studies to gain a better understanding of the drug loading, drug-release kinetics and cell-based efficacy of RBCm-cloaked NPs.Materials & methodsTwo strategies for loading doxorubicin into the RBCm-cloaked NPs were compared: physical encapsulation and chemical conjugation. In vitro efficacy was examined using the acute myeloid leukemia cell line, Kasumi-1.ResultsIt was found that the chemical conjugation strategy resulted in a more sustained drug release profile, and that the RBCm cloak provided a barrier, retarding the outward diffusion of encapsulated drug molecules. It was also demonstrated that RBCm-cloaked NPs exhibit higher toxicity in comparison with free doxorubicin.ConclusionThese results indicate that the RBCm-cloaked NPs hold great promise to become a valuable drug-delivery platform for the treatment of various diseases such as blood cancers

Erythrocyte membrane-cloaked polymeric nanoparticles for controlled drug loading and release.

AimPolymeric nanoparticles (NPs) cloaked by red blood cell membrane (RBCm) confer the combined advantage of both long circulation lifetime and controlled drug release. The authors carried out studies to gain a better understanding of the drug loading, drug-release kinetics and cell-based efficacy of RBCm-cloaked NPs.Materials & methodsTwo strategies for loading doxorubicin into the RBCm-cloaked NPs were compared: physical encapsulation and chemical conjugation. In vitro efficacy was examined using the acute myeloid leukemia cell line, Kasumi-1.ResultsIt was found that the chemical conjugation strategy resulted in a more sustained drug release profile, and that the RBCm cloak provided a barrier, retarding the outward diffusion of encapsulated drug molecules. It was also demonstrated that RBCm-cloaked NPs exhibit higher toxicity in comparison with free doxorubicin.ConclusionThese results indicate that the RBCm-cloaked NPs hold great promise to become a valuable drug-delivery platform for the treatment of various diseases such as blood cancers

CD4+ T cell-mimicking nanoparticles encapsulating DIABLO/SMAC mimetics broadly neutralize HIV-1 and selectively kill HIV-1-infected cells.

HIV-1 is a major global health challenge. The development of an effective vaccine and a therapeutic cure are top priorities. The creation of vaccines that focus an antibody response toward a particular epitope of a protein has shown promise, but the genetic diversity of HIV-1 stymies this progress. Therapeutic strategies that provide effective and broad-spectrum neutralization against HIV-1 infection are highly desirable. Methods: We investigated the potential of nanoengineered CD4+ T cell membrane-coated nanoparticles (TNP) encapsulating the DIABLO/SMAC mimetics LCL-161 or AT-406 (also known as SM-406 or Debio 1143) to both neutralize HIV-1 and selectively kill HIV-1-infected resting CD4+ T cells and macrophages. Results: DIABLO/SMAC mimetic-loaded TNP displayed outstanding neutralizing breadth and potency, and selectively kill HIV-1-infected cells via autophagy-dependent apoptosis while having no drug-induced off-target or cytotoxic effects on bystander cells. Genetic inhibition of early stages of autophagy abolishes this effect. Conclusion: DIABLO/SMAC mimetic loaded TNP have the potential to be used as therapeutic agents to neutralize cell-free HIV-1 and to kill specifically HIV-1-infected cells as part of an HIV-1 cure strategy

Nanoparticle Functionalization with Platelet Membrane Enables Multifactored Biological Targeting and Detection of Atherosclerosis.

Cardiovascular disease represents one of the major causes of death across the global population. Atherosclerosis, one of its most common drivers, is characterized by the gradual buildup of arterial plaque over time, which can ultimately lead to life-threatening conditions. Given the impact of the disease on public health, there is a great need for effective and noninvasive imaging modalities that can provide valuable information on its biological underpinnings during development. Here, we leverage the role of platelets in atherogenesis to design nanocarriers capable of targeting multiple biological elements relevant to plaque development. Biomimetic nanoparticles are prepared by coating platelet membrane around a synthetic nanoparticulate core, the product of which is capable of interacting with activated endothelium, foam cells, and collagen. The effects are shown to be exclusive to platelet membrane-coated nanoparticles. These biomimetic nanocarriers are not only capable of efficiently localizing to well-developed atherosclerotic plaque, but can also target subclinical regions of arteries susceptible to plaque formation. Using a commonly employed magnetic resonance imaging contrast agent, live detection is demonstrated using an animal model of atherosclerosis. Ultimately, this strategy may be leveraged to better assess the development of atherosclerosis, offering additional information to help clinicians better manage the disease

Multiantigenic Nanotoxoids for Antivirulence Vaccination against Antibiotic-Resistant Gram-Negative Bacteria

Infections caused by multidrug-resistant Gram-negative bacteria have emerged as a major threat to public health worldwide. The high mortality and prevalence, along with the slow pace of new antibiotic discovery, highlight the necessity for new disease management paradigms. Here, we report on the development of a multiantigenic nanotoxoid vaccine based on macrophage membrane-coated nanoparticles for eliciting potent immunity against pathogenic Pseudomonas aeruginosa. The design of this biomimetic nanovaccine leverages the specific role of macrophages in clearing pathogens and their natural affinity for various virulence factors secreted by the bacteria. It is demonstrated that the macrophage nanotoxoid is able to display a wide range of P. aeruginosa antigens, and the safety of the formulation is confirmed both in vitro and in vivo. When used to vaccinate mice via different administration routes, the nanotoxoid is capable of eliciting strong humoral immune responses that translate into enhanced protection against live bacterial infection in a pneumonia model. Overall, the work presented here provides new insights into the design of safe, multiantigenic antivirulence vaccines using biomimetic nanotechnology and the application of these nanovaccines toward the prevention of difficult-to-treat Gram-negative infections