Diana Dehaini

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.

Biomimetic strategies for targeted nanoparticle delivery

Abstract Nanoparticle‐based drug delivery and imaging platforms have become increasingly popular over the past several decades. Among different design parameters that can affect their performance, the incorporation of targeting functionality onto nanoparticle surfaces has been a widely studied subject. Targeted formulations have the ability to improve efficacy and function by positively modulating tissue localization. Many methods exist for creating targeted nanoformulations, including the use of custom biomolecules such as antibodies or aptamers. More recently, a great amount of focus has been placed on biomimetic targeting strategies that leverage targeting interactions found directly in nature. Such strategies, which have been painstakingly selected over time by the process of evolution to maximize functionality, oftentimes enable scientists to forgo the specialized discovery processes associated with many traditional ligands and help to accelerate development of novel nanoparticle formulations. In this review, we categorize and discuss in‐depth recent works in this growing field of bioinspired research.

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

AIM Polymeric 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 & METHODS Two 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. RESULTS It 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. CONCLUSION These 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–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.

Safe and immunocompatible nanocarriers cloaked in RBC membranes for drug delivery to treat solid tumors

The therapeutic potential of nanoparticle-based drug carriers depends largely on their ability to evade the host immune system while delivering their cargo safely to the site of action. Of particular interest are simple strategies for the functionalization of nanoparticle surfaces that are both inherently safe and can also bestow immunoevasive properties, allowing for extended blood circulation times. Here, we evaluated a recently reported cell membrane-coated nanoparticle platform as a drug delivery vehicle for the treatment of a murine model of lymphoma. These biomimetic nanoparticles, consisting of a biodegradable polymeric material cloaked with natural red blood cell membrane, were shown to efficiently deliver a model chemotherapeutic, doxorubicin, to solid tumor sites for significantly increased tumor growth inhibition compared with conventional free drug treatment. Importantly, the nanoparticles also showed excellent immunocompatibility as well as an advantageous safety profile compared with the free drug, making them attractive for potential translation. This study demonstrates the promise of using a biomembrane-coating approach as the basis for the design of functional, safe, and immunocompatible nanocarriers for cancer drug delivery.

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.

Remote Loading of Small Molecule Therapeutics into Cholesterol-Enriched Cell Membrane-Derived Vesicles

The increasing popularity of biomimetic design principles in nanomedicine has led to therapeutic platforms with enhanced performance and biocompatibility. This includes the use of naturally derived cell membranes, which can bestow nanocarriers with cell-specific functionalities. Herein, we report on a strategy enabling efficient encapsulation of drugs via remote loading into membrane vesicles derived from red blood cells. This is accomplished by supplementing the membrane with additional cholesterol, stabilizing the nanostructure and facilitating the retention of a pH gradient. We demonstrate the loading of two model drugs: the chemotherapeutic doxorubicin and the antibiotic vancomycin. The therapeutic implications of these natural, remote-loaded nanoformulations are studied both in vitro and in vivo using animal disease models. Ultimately, this approach could be used to design new biomimetic nanoformulations with higher efficacy and improved safety profiles.

Hybrid biomembrane–functionalized nanorobots for concurrent removal of pathogenic bacteria and toxins

Nanorobots with red blood cell–platelet hybrid membranes accelerated targeting and detoxification of biological threats. With the rapid advancement of robotic research, it becomes increasingly interesting and important to develop biomimetic micro- or nanorobots that translate biological principles into robotic systems. We report the design, construction, and evaluation of a dual–cell membrane–functionalized nanorobot for multipurpose removal of biological threat agents, particularly concurrent targeting and neutralization of pathogenic bacteria and toxins. Specifically, we demonstrated ultrasound-propelled biomimetic nanorobots consisting of gold nanowires cloaked with a hybrid of red blood cell (RBC) membranes and platelet (PL) membranes. Such hybrid cell membranes have a variety of functional proteins associated with human RBCs and PLs, which give the nanorobots a number of attractive biological capabilities, including adhesion and binding to PL-adhering pathogens (e.g., Staphylococcus aureus bacteria) and neutralization of pore-forming toxins (e.g., α-toxin). In addition, the biomimetic nanorobots displayed rapid and efficient prolonged acoustic propulsion in whole blood, with no apparent biofouling, and mimicked the movement of natural motile cells. This propulsion enhanced the binding and detoxification efficiency of the robots against pathogens and toxins. Overall, coupling these diverse biological functions of hybrid cell membranes with the fuel-free propulsion of the nanorobots resulted in a dynamic robotic system for efficient isolation and simultaneous removal of different biological threats, an important step toward the creation of a broad-spectrum detoxification robotic platform.

Neutrophil membrane-coated nanoparticles inhibit synovial inflammation and alleviate joint damage in inflammatory arthritis

Rheumatoid arthritis is a common chronic inflammatory disorder and a major cause of disability. Despite the progress made with recent clinical use of anti-cytokine biologics, the response rate of rheumatoid arthritis treatment remains unsatisfactory, owing largely to the complexity of cytokine interactions and the multiplicity of cytokine targets. Here, we show a nanoparticle-based broad-spectrum anti-inflammatory strategy for rheumatoid arthritis management. By fusing neutrophil membrane onto polymeric cores, we prepare neutrophil membrane-coated nanoparticles that inherit the antigenic exterior and associated membrane functions of the source cells, which makes them ideal decoys of neutrophil-targeted biological molecules. It is shown that these nanoparticles can neutralize proinflammatory cytokines, suppress synovial inflammation, target deep into the cartilage matrix, and provide strong chondroprotection against joint damage. In a mouse model of collagen-induced arthritis and a human transgenic mouse model of arthritis, the neutrophil membrane-coated nanoparticles show significant therapeutic efficacy by ameliorating joint damage and suppressing overall arthritis severity.Neutrophil membrane-coated nanoparticles reduce neutrophil-mediated inflammation in animal models of rheumatoid arthritis by acting as decoy devices and interacting with immunoregulatory agents targeted towards these cells.

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.