Single Low-Dose Nanovaccine for Long-Term Protection against Anthrax Toxins.

Anthrax infections caused by Bacillus anthracis are an ongoing bioterrorism and livestock threat worldwide. Current approaches for management, including extended passive antibody transfusion, antibiotics, and prophylactic vaccination, are often cumbersome and associated with low patient compliance. Here, we report on the development of an adjuvanted nanotoxoid vaccine based on macrophage membrane-coated nanoparticles bound with anthrax toxins. This design leverages the natural binding interaction of protective antigen, a key anthrax toxin, with macrophages. In a murine model, a single low-dose vaccination with the nanotoxoids generates long-lasting immunity that protects against subsequent challenge with anthrax toxins. Overall, this work provides a new approach to address the ongoing threat of anthrax outbreaks and bioterrorism by taking advantage of an emerging biomimetic nanotechnology.

Organotropic Targeting of Biomimetic Nanoparticles to Treat Lung Disease.

Active targeting strategies aimed at improving drug homing while reducing systemic toxicity are widely being pursued in the growing field of nanomedicine. While they can be effective, these approaches often require the identification of cell-specific targets and in-depth knowledge of receptor binding interactions. More recently, there has been significant interest in biomimetic nanoformulations capable of replicating the properties of naturally occurring systems. In particular, the advent of cell membrane coating nanotechnology has enabled researchers to leverage the inherent tropisms displayed by living cells, bypassing many of the challenges associated with traditional bottom-up nanoengineering. In this work, we report on a biomimetic organotropic nanodelivery system for localizing therapeutic payloads to the lungs. Metastatic breast cancer exosomes, which are lung tropic due to their unique surface marker expression profile, are used to coat nanoparticle cores loaded with the anti-inflammatory drug dexamethasone. In vivo, these nanoparticles demonstrate enhanced accumulation in lung tissue and significantly reduce proinflammatory cytokine burden in a lung inflammation model. Overall, this work highlights the potential of using biomimetic organ-level delivery strategies for the management of certain disease conditions.

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.

A modular approach to enhancing cell membrane-coated nanoparticle functionality using genetic engineering.

Since their initial development, cell membrane-coated nanoparticles (CNPs) have become increasingly popular in the biomedical field. Despite their inherent versatility and ability to enable complex biological applications, there is considerable interest in augmenting the performance of CNPs through the introduction of additional functionalities. Here we demonstrate a genetic-engineering-based modular approach to CNP functionalization that can encompass a wide range of ligands onto the nanoparticle surface. The cell membrane coating is engineered to express a SpyCatcher membrane anchor that can readily form a covalent bond with any moiety modified with SpyTag. To demonstrate the broad utility of this technique, three unique targeted CNP formulations are generated using different classes of targeting ligands, including a designed ankyrin repeat protein, an affibody and a single-chain variable fragment. In vitro, the modified nanoparticles exhibit enhanced affinity towards cell lines overexpressing the cognate receptors for each ligand. When formulated with a chemotherapeutic payload, the modularly functionalized nanoparticles display strong targeting ability and growth suppression in a murine tumour xenograft model of ovarian cancer. Our data suggest genetic engineering offers a feasible approach for accelerating the development of multifunctional CNPs for a broad range of biomedical applications.

A Microstirring Oral Pill for Improving the Glucose-Lowering Effect of Metformin.

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia due to persistent insulin resistance, resulting in elevated blood glucose levels. Metformin is the most prescribed oral drug for lowering high blood glucose levels in T2DM patients. However, it is poorly absorbed and has low bioavailability. Here, we introduce magnesium-based microstirrers to a metformin-containing pill matrix to enhance the glucose-lowering effect of metformin. The resulting microstirring pill possesses a built-in mixing capability by creating local fluid transport upon interacting with biological fluid to enable fast pill disintegration and drug release along with accelerated metformin delivery. In vivo glucose tolerance testing using a murine model demonstrates that the metformin microstirring pill significantly improves therapeutic efficacy, lowering blood glucose levels after a meal more rapidly compared to a regular metformin pill without active stirring. As a result, the microstirrers allow for dose sparing, providing effective therapeutic efficacy at a lower drug dosage than passive metformin pills. These encouraging results highlight the versatility of this simple yet elegant microstirring pill technology, which enhances drug absorption after gastrointestinal delivery to improve therapeutic efficacy.

Bacterial membrane vesicles for vaccine applications.

Vaccines have been highly successful in the management of many diseases. However, there are still numerous illnesses, both infectious and noncommunicable, for which there are no clinically approved vaccine formulations. While there are unique difficulties that must be overcome in the case of each specific disease, there are also a number of common challenges that have to be addressed for effective vaccine development. In recent years, bacterial membrane vesicles (BMVs) have received increased attention as a potent and versatile vaccine platform. BMVs are inherently immunostimulatory and are able to activate both innate and adaptive immune responses. Additionally, BMVs can be readily taken up and processed by immune cells due to their nanoscale size. Finally, BMVs can be modified in a variety of ways, including by genetic engineering, cargo loading, and nanoparticle coating, in order to create multifunctional platforms that can be leveraged against different diseases. Here, an overview of the interactions between BMVs and immune cells is provided, followed by discussion on the applications of BMV vaccine nanotechnology against bacterial infections, viral infections, and cancers.

Nanotoxoid vaccination protects against opportunistic bacterial infections arising from immunodeficiency.

The rise in nosocomial infections caused by multidrug-resistant pathogens is a major public health concern. Patients taking immunosuppressants or chemotherapeutics are naturally more susceptible to infections. Thus, strategies for protecting immunodeficient individuals from infections are of great importance. Here, we investigate the effectiveness of a biomimetic nanotoxoid vaccine in defending animals with immunodeficiency against Pseudomonas aeruginosa. The nanotoxoids use a macrophage membrane coating to sequester and safely present bacterial virulence factors that would otherwise be too toxic to administer. Vaccination with the nanoformulation results in rapid and long-lasting immunity, protecting against lethal infections despite severe immunodeficiency. The nanovaccine can be administered through multiple routes and is effective in both pneumonia and septicemia models of infection. Mechanistically, protection is mediated by neutrophils and pathogen-specific antibodies. Overall, nanotoxoid vaccination is an attractive strategy to protect vulnerable patients and could help to mitigate the threat posed by antibiotic-resistant superbugs.

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.

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.

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.

Zinc Microrocket Pills: Fabrication and Characterization toward Active Oral Delivery.

Here the fabrication of a zinc (Zn) microrocket pill is reported, and its unique features toward active and enhanced oral delivery application are demonstrated. By loading Zn-based tubular microrockets into an orally administrable pill formulation, the resulting Zn microrocket pill can rapidly dissolve in the stomach, releasing numerous encapsulated Zn microrockets that are instantaneously activated and then propel in the gastric fluid. The released Zn microrockets display efficient propulsion without being affected by the presence of the inactive excipient materials of the pill. An in vivo retention study performed in mice clearly shows that the active pill dissolution and powerful acid-driven Zn microrocket propulsion greatly enhance the microrocket retention within the gastric tissue without causing toxic effects. By combining the active delivery feature of Zn microrockets with the oral administration of a pill, the Zn microrocket pill holds considerable potential for active oral delivery of various therapeutics for diverse medical applications.

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.

Biomimetic Nanoparticle Vaccines for Cancer Therapy.

It is currently understood that, in order for a tumor to successfully grow, it must evolve means of evading immune surveillance. In the past several decades, researchers have leveraged increases in our knowledge of tumor immunology to develop therapies capable of augmenting endogenous immunity and eliciting strong antitumor responses. In particular, the goal of anticancer vaccination is to train the immune system to properly utilize its own resources in the fight against cancer. Although attractive in principle, there are currently only limited examples of anticancer vaccines that have been successfully translated to the clinic. Recently, there has been a significant push towards the use of nanotechnology for designing vaccine candidates that exhibit enhanced potency and specificity. In this progress report, we discuss recent developments in the field of anticancer nanovaccines. By taking advantage of the flexibility offered by nanomedicine to purposefully program immune responses, this new generation of vaccines has the potential to address many of the hurdles facing traditional platforms. A specific emphasis is placed on the emergence of cell membrane-coated nanoparticles, a novel biomimetic platform that can be used to generate personalized nanovaccines that elicit strong, multi-antigenic antitumor responses.

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 Nanoemulsions for Oxygen Delivery In Vivo.

Blood transfusion is oftentimes required for patients suffering from acute trauma or undergoing surgical procedures in order to help maintain the body's oxygen levels. The continued demand worldwide for blood products is expected to put significant strain on available resources and infrastructure. Unfortunately, efforts to develop viable alternatives to human red blood cells for transfusion are generally unsuccessful. Here, a hybrid natural-synthetic nanodelivery platform that combines the biocompatibility of the natural RBC membrane with the oxygen-carrying ability of perfluorocarbons is reported. The resulting formulation can be stored long-term and exhibits a high capacity for oxygen delivery, helping to mitigate the effects of hypoxia in vitro. In an animal model of hemorrhagic shock, mice are resuscitated at an efficacy comparable to whole blood infusion. By leveraging the advantageous properties of its constituent parts, this biomimetic oxygen delivery system may have the potential to address a critical need in the clinic.