Ashley V. Kroll

Nanoparticle biointerfacing by platelet membrane cloaking

Development of functional nanoparticles can be encumbered by unanticipated material properties and biological events, which can affect nanoparticle effectiveness in complex, physiologically relevant systems. Despite the advances in bottom-up nanoengineering and surface chemistry, reductionist functionalization approaches remain inadequate in replicating the complex interfaces present in nature and cannot avoid exposure of foreign materials. Here we report on the preparation of polymeric nanoparticles enclosed in the plasma membrane of human platelets, which are a unique population of cellular fragments that adhere to a variety of disease-relevant substrates. The resulting nanoparticles possess a right-side-out unilamellar membrane coating functionalized with immunomodulatory and adhesion antigens associated with platelets. Compared to uncoated particles, the platelet membrane-cloaked nanoparticles have reduced cellular uptake by macrophage-like cells and lack particle-induced complement activation in autologous human plasma. The cloaked nanoparticles also display platelet-mimicking properties such as selective adhesion to damaged human and rodent vasculatures as well as enhanced binding to platelet-adhering pathogens. In an experimental rat model of coronary restenosis and a mouse model of systemic bacterial infection, docetaxel and vancomycin, respectively, show enhanced therapeutic efficacy when delivered by the platelet-mimetic nanoparticles. The multifaceted biointerfacing enabled by the platelet membrane cloaking method provides a new approach in developing functional nanoparticles for disease-targeted delivery.

Erythrocyte–Platelet Hybrid Membrane Coating for Enhanced Nanoparticle Functionalization

Cell-membrane-coated nanoparticles have recently been studied extensively for their biological compatibility, retention of cellular properties, and adaptability to a variety of therapeutic and imaging applications. This class of nanoparticles, which has been fabricated with a variety of cell membrane coatings, including those derived from red blood cells (RBCs), platelets, white blood cells, cancer cells, and bacteria, exhibit properties that are characteristic of the source cell. In this study, a new type of biological coating is created by fusing membrane material from two different cells, providing a facile method for further enhancing nanoparticle functionality. As a proof of concept, the development of dual-membrane-coated nanoparticles from the fused RBC membrane and platelet membrane is demonstrated. The resulting particles, termed RBC-platelet hybrid membrane-coated nanoparticles ([RBC-P]NPs), are thoroughly characterized, and it is shown that they carry properties of both source cells. Further, the [RBC-P]NP platform exhibits long circulation and suitability for further in vivo exploration. The reported strategy opens the door for the creation of biocompatible, custom-tailored biomimetic nanoparticles with varying hybrid functionalities, which may be used to overcome the limitations of current nanoparticle-based therapeutic and imaging platforms.

Nanoparticle‐Based Manipulation of Antigen‐Presenting Cells for Cancer Immunotherapy

Immunotherapeutic approaches for treating cancer overall have been receiving a considerable amount of interest due to the recent approval of several clinical formulations. Among the different modalities, anticancer vaccination acts by training the body to endogenously generate a response against tumor cells. However, despite the large amount of work that has gone into the development of such vaccines, the near absence of clinically approved formulations highlights the many challenges facing those working in the field. The generation of potent endogenous anticancer responses poses unique challenges due to the similarity between cancer cells and normal, healthy cells. As researchers continue to tackle the limited efficacy of vaccine formulations, fresh and novel approaches are being sought after to address many of the underlying problems. Here the application of nanoparticle technology towards the development of anticancer vaccines is discussed. Specifically, there is a focus on the benefits of using such strategies to manipulate antigen presenting cells (APCs), which are essential to the vaccination process, and how nanoparticle-based platforms can be rationally engineered to elicit appropriate downstream immune responses.

In Situ Capture of Bacterial Toxins for Antivirulence Vaccination

Antivirulence vaccination is a promising strategy for addressing bacterial infection that focuses on removing the harmful toxins produced by bacteria. However, a major challenge for creating vaccines against biological toxins is that the vaccine potency is often limited by lack of antigenic breadth, as most formulations have focused on single antigens, while most bacteria secrete a plethora of toxins. Here, a facile approach for generating multiantigenic nanotoxoids for use as vaccines against pathogenic bacteria by leveraging the natural affinity of virulence factors for cellular membranes is reported. Specifically, multiple virulent toxins from bacterial protein secretions are concurrently and naturally entrapped using a membrane-coated nanosponge construct. The resulting multivalent nanotoxoids are capable of delivering virulence factors together, are safe both in vitro and in vivo, and can elicit functional immunity capable of combating live bacterial infections in a mouse model. Despite containing the same bacterial antigens, the reported nanotoxoid formulation consistently outperforms a denatured protein preparation in all of the metrics studied, which underscores the utility of biomimetic nanoparticle-based neutralization and delivery. Overall this strategy helps to address major hurdles in the design of antivirulence vaccines, enabling increased antigenic breadth while maintaining safety.

Nanoparticulate Delivery of Cancer Cell Membrane Elicits Multiantigenic Antitumor Immunity

Anticancer vaccines train the bodys own immune system to recognize and eliminate malignant cells based on differential antigen expression. While conceptually attractive, clinical efficacy is lacking given several key challenges stemming from the similarities between cancerous and healthy tissue. Ideally, an effective vaccine formulation would deliver multiple tumor antigens in a fashion that potently stimulates endogenous immune responses against those antigens. Here, it is reported on the fabrication of a biomimetic, nanoparticulate anticancer vaccine that is capable of delivering autologously derived tumor antigen material together with a highly immunostimulatory adjuvant. The two major components, tumor antigens and adjuvant, are presented concurrently in a fashion that maximizes their ability to promote effective antigen presentation and activation of downstream immune processes. Ultimately, it is demonstrated that the formulation can elicit potent antitumor immune responses in vivo. When combined with additional immunotherapies such as checkpoint blockades, the nanovaccine demonstrates substantial therapeutic effect. Overall, the work represents the rational application of nanotechnology for immunoengineering and can provide a blueprint for the future development of personalized, autologous anticancer vaccines with broad applicability.

Cell Membrane Coating Nanotechnology

Nanoparticle-based therapeutic, prevention, and detection modalities have the potential to greatly impact how diseases are diagnosed and managed in the clinic. With the wide range of nanomaterials available, the rational design of nanocarriers on an application-specific basis has become increasingly commonplace. Here, a comprehensive overview is provided on an emerging platform: cell-membrane-coating nanotechnology. As a fundamental unit of biology, cells carry out a wide range of functions, including the remarkable ability to interface and interact with their surrounding environment. Instead of attempting to replicate such functions via synthetic techniques, researchers are now directly leveraging naturally derived cell membranes as a means of bestowing nanoparticles with enhanced biointerfacing capabilities. This top-down technique is facile, highly generalizable, and has the potential to greatly augment existing nanocarriers. Further, the introduction of a natural membrane substrate onto nanoparticles surfaces has enabled additional applications beyond those traditionally associated with nanomedicine. Despite its relative youth, there exists an impressive body of literature on cell membrane coating, which is covered here in detail. Overall, there is still significant room for development, as researchers continue to refine existing workflows while finding new and exciting applications that can take advantage of this developing technology.

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.

Nano-immunoengineering: Nanoparticle-Based Manipulation of Antigen-Presenting Cells for Cancer Immunotherapy (Small 41/2015)

On page 5483, L. Zhang and co-workers describe the process of nanoparticle-mediated antigen presentation. A dendritic cell takes up cell membrane-coated nanoparticles that are loaded with an immunological adjuvant. After uptake, the tumor antigens on the nanoparticle-stabilized membrane are processed and presented on the surface of the dendritic cell. Meanwhile, the adjuvant is released and causes the dendritic cell to mature, ultimately enabling it to activate tumor antigen-specific T cells (shown here as green).