Liangfang Zhang

The integration of microorganisms and engineered artificial components has shown considerable promise for creating biohybrid microrobots. The unique features of microalgae make them attractive candidates as natural actuation materials for the design of biohybrid microrobotic systems. In this review, microalgae‐based biohybrid microrobots are introduced for diverse biomedical and environmental applications. The distinct propulsion and phototaxis behaviors of green microalgae, as well as important properties from other photosynthetic microalga systems (blue‐green algae and diatom) that are crucial to constructing powerful biohybrid microrobots, will be described first. Then the focus is on chemical and physical routes for functionalizing the algae surface with diverse reactive materials toward the fabrication of advanced biohybrid microalgae robots. Finally, representative applications of such algae‐driven …

The etiology of cancers is multifactorial, with certain bacteria established as contributors to carcinogenesis. As the understanding of carcinogenic bacteria deepens, interest in cancer treatment through bacterial eradication is growing. Among emerging antibacterial platforms, cell membrane-coated nanoparticles (CNPs), constructed by enveloping synthetic substrates with natural cell membranes, exhibit significant promise in overcoming challenges encountered by traditional antibiotics. This article reviews recent advancements in developing CNPs for targeting carcinogenic bacteria. It first summarizes the mechanisms of carcinogenic bacteria and the status of cancer treatment through bacterial eradication. Then, it reviews engineering strategies for developing highly functional and multitasking CNPs and examines the emerging applications of CNPs in combating carcinogenic bacteria. These applications include …

The multifaceted functions of platelets in various physiological processes have long inspired the development of therapeutic nanoparticles that mimic specific platelet features for disease treatment. Here, the development and characterization of platelet membrane‐derived nanodiscs (PLT‐NDs) as platelet decoys for biological neutralization is reported. In one application, PLT‐NDs effectively bind with anti‐platelet autoantibodies, thus blocking them from interacting with platelets. In a mouse model of thrombocytopenia, PLT‐NDs successfully neutralize pathological anti‐platelet antibodies, preventing platelet depletion and maintaining hemostasis. In another application, PLT‐NDs effectively neutralize the cytotoxicity of bacterial virulence factors secreted by methicillin‐resistant Staphylococcus aureus (MRSA). In a mouse model of MRSA infection, treatment with PLT‐NDs leads to significant survival benefits for the …

Neurotoxins present a substantial threat to human health and security as they disrupt and damage the nervous system. Their potent and structurally diverse nature poses challenges in developing effective countermeasures. In this study, a unique nanoparticle design that combines dual‐biomimicry mechanisms to enhance the detoxification efficacy of neurotoxins is introduced. Using saxitoxin (STX), one of the deadliest neurotoxins, and its natural binding protein saxiphilin (Sxph) as a model system, human neuronal membrane‐coated and Sxph‐loaded metal–organic framework (MOF) nanosponges (denoted “Neuron‐MOF/Sxph‐NS”) are successfully developed. The resulting Neuron‐MOF/Sxph‐NS exhibit a biomimetic design that not only emulates host neurons for function‐based detoxification through the neuronal membrane coating, but also mimics toxin‐resistant organisms by encapsulating the Sxph protein …

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 …

There is growing interest in developing cell membrane‐coated nanoparticles (CNPs) for unique host cell mimicry and therapeutic applications. The continuous evolution of this technology has motivated the coating of nanoparticles with hybrid membranes originating from diverse cell types. The resulting hybrid cell membrane‐coated nanoparticles (hybrid CNPs) exhibit a higher level of synergy among multifunctionalities with better multitasking capabilities than their monotypic membrane‐coated counterparts. This advancement has catalyzed the initiation of numerous research opportunities, marking the advent of a promising frontier in therapeutic applications. This review outlines emerging biomedical applications of hybrid CNPs, focusing on drug targeting, immune modulation, biological neutralization, and disease diagnosis. Within each application, the review underscores how the strategic hybridization of distinct …

Disclosed are methods, materials and devices that pertain to a microstirring pill technology with built-in mixing capability for oral drug delivery that greatly enhances bioavailability of its therapeutic payload. In some aspects, a drug delivery device includes a pill matrix dissolvable in a fluid medium and loaded with a plurality of drug payloads; and a plurality of micro stirrers embedded in the pill matrix and configured to create a local fluid transport upon interacting with a biological fluid surrounding the microstirring pill.

Vaccination has become an increasingly attractive strategy for protecting against antibiotic-resistant infections. Nanovaccines based on the outer membrane from Gram-negative bacteria are appealing due to their multiantigenic nature and inherent immunogenicity. Here, we develop cellular nanodiscs made of bacterial outer membrane (OM-NDs), as a platform for antibacterial vaccination. Using Pseudomonas aeruginosa as a model pathogen, the resulting OM-NDs can effectively interact with antigen-presenting cells, exhibiting accelerated uptake and an improved capacity for immune stimulation. With their small size, the OM-NDs are also capable of efficiently transporting to the lymph nodes after in vivo administration. As a result, the nanovaccine is effective at eliciting potent humoral and cellular immune responses against P. aeruginosa. In a murine model of pneumonia, immunization with OM-NDs confers …

Nanodiscs are a compelling nanomedicine platform due to their ultrasmall size and distinct disc shape. Current nanodisc formulations are made primarily with synthetic lipid bilayers and proteins. Here, we report a cellular nanodisc made with human red blood cell (RBC) membrane (denoted “RBC‐ND”) and show its effective neutralization against bacterial toxins. In vitro, RBC‐ND neutralizes the hemolytic activity and cytotoxicity caused by purified α‐toxin or complex whole secreted proteins (wSP) from methicillin‐resistant Staphylococcus aureus bacteria. In vivo, RBC‐ND confers significant survival benefits for mice intoxicated with α‐toxin or wSP in both therapeutic and prevention regimens. Moreover, RBC‐ND shows good biocompatibility and biosafety in vivo. Overall, RBC‐ND distinguishes itself by inheriting the biological functions of the source cell membrane for bioactivity. The design strategy of RBC‐ND can …

Cell membrane-based nanovaccines have demonstrated attractive features due to their inherently multiantigenic nature and ability to be formulated with adjuvants. Here, we report on cellular nanodiscs fabricated from cancer cell membranes and incorporated with a lipid-based adjuvant for antitumor vaccination. The cellular nanodiscs, with their small size and discoidal shape, are readily taken up by antigen-presenting cells and drain efficiently to the lymph nodes. Due to its highly immunostimulatory properties, the nanodisc vaccine effectively stimulates the immune system and promotes tumor-specific immunity. Using a murine colorectal cancer model, strong control of tumor growth is achieved in both prophylactic and therapeutic settings, particularly in combination with checkpoint blockades. Considerable therapeutic efficacy is also observed in treating a weakly immunogenic metastatic melanoma model. This …

The rise of antibiotic resistance has caused the prevention and treatment of bacterial infections to be less effective. Therefore, researchers turn to nanomedicine for novel and effective antibacterial therapeutics. The effort resulted in the first‐generation antibacterial nanoparticles featuring the ability to improve drug tolerability, circulation half‐life, and efficacy. Toward developing the next‐generation antibacterial nanoparticles, researchers have integrated design elements that emphasize physical, broad‐spectrum, biomimetic, and antivirulence mechanisms. This review highlights four emerging antibacterial nanoparticle designs: inorganic antibacterial nanoparticles, responsive antibacterial nanocarriers, virulence nanoscavengers, and antivirulence nanovaccines. Examples in each design category are selected and reviewed, and their structure–function relationships are discussed. These emerging designs open the …

2020-10-27 Assigned to THE BRIGHAM AND WOMEN'S HOSPITAL, INC. reassignment THE BRIGHAM AND WOMEN'S HOSPITAL, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ALEXIS, FRANK, FAROKHZAD, OMID C.

Recently, there has been high interest in developing metal-organic framework (MOF) nanoparticles (NPs) for delivering therapeutic proteins, propelled mainly by the unique hierarchical porous structures of MOFs for protein encapsulation. Novel design strategies have emerged for broad therapeutic applications and clinical translations, leading to multifunctional MOF-NPs with improved biointerfacing capabilities and higher potency. This review summarizes recent MOF-NP designs specifically for protein delivery. The summary focuses on four design categories, including environment-responsive MOF-NPs for on-demand protein delivery, cell membrane-coated MOF-NPs for biomimetic protein delivery, cascade reaction-incorporated MOF-NPs for combinatorial protein delivery, and composite MOF-NPs for intelligent protein delivery. The major challenges and opportunities in using MOF-NPs for protein delivery are …

In recent years, nanoparticles derived from cellular membranes have been increasingly explored for the prevention and treatment of human disease. With their flexible design and ability to interface effectively with the surrounding environment, these biomimetic nanoparticles can outperform their traditional synthetic counterparts. As their popularity has increased, researchers have developed novel ways to modify the nanoparticle surface to introduce new or enhanced capabilities. Moving beyond naturally occurring materials derived from wild-type cells, genetic manipulation has proven to be a robust and flexible method by which nanoformulations with augmented functionalities can be generated. In this review, an overview of genetic engineering approaches to express novel surface proteins is provided, followed by a discussion on the various biomedical applications of genetically modified cellular nanoparticles.

Nanoparticles coated with natural cell membranes have emerged as a promising class of biomimetic nanomedicine with significant clinical potential. Among them, macrophage membrane‐coated nanoparticles hold particular appeal due to their versatility in drug delivery and biological neutralization applications. This study employs a genetic engineering approach to enhance their in vivo residence times, aiming to further improve their performance. Specifically, macrophages are engineered to express proline‐alanine‐serine (PAS) peptide chains, which provide additional protection against opsonization and phagocytosis. The resulting modified nanoparticles demonstrate prolonged residence times when administered intravenously or introduced intratracheally, surpassing those coated with the wild‐type membrane. The longer residence times also contribute to enhanced nanoparticle efficacy in inhibiting …

Over the last two decades, nanomedicine has rapidly grown as a field that utilizes nanoscale materials for biomedical applications. With their ability to improve control over the localization and release of therapeutic agents, nanocarriers offer a safer and more effective approach for addressing a wide range of diseases. 1 Along these lines, cell membrane coating is an emerging technology that has been leveraged to significantly improve the functionality of nanoparticulate platforms (Figure 1). 2 Cell membrane-coated nanoparticles (CNPs) possess many attributes that make them suitable for in vivo delivery applications, including improved biocompatibility, active targeting, increased stability, and reduced toxicity. As Fang et al. discussed recently in Nature Reviews Clinical Oncology, CNPs have become a promising tool for cancer treatment. 3One major advantage of employing CNPs for drug delivery is their inherent …

Inflammatory bowel disease (IBD) is a chronic gastrointestinal tract disorder characterized by uncontrolled inflammatory responses to the disrupted intestinal epithelial barrier and gut microbiome dysbiosis. Currently available small-molecule immunosuppressive agents and anticytokine biologics show limited potency, mainly due to the complexity of the inflammatory network involved in IBD. Here, we develop an oral formulation of macrophage membrane-coated nanoparticles capsulated in enteric polymer-coated gelatin capsules (denoted “cp-MΦ-NPs”) for IBD treatment. The capsules protect the nanoparticles from gastric degradation and allow for targeted delivery to the colon. At the inflamed colon, cp-MΦ-NPs act as macrophage decoys that bind and neutralize pro-inflammatory cytokines. The in vivo treatment efficacy of cp-MΦ-NPs is tested in a mouse model of dextran sulfate sodium-induced colitis. In both …

Traditional cancer therapeutics, such as chemotherapies, are often limited by their non-specific nature, causing harm to non-malignant tissues. Over the past several decades, nanomedicine researchers have sought to address this challenge by developing nanoscale platforms capable of more precisely delivering drug payloads. Cell membrane-coated nanoparticles (CNPs) are an emerging class of nanocarriers that have demonstrated considerable promise for biomedical applications. Consisting of a synthetic nanoparticulate core camouflaged by a layer of naturally derived cell membranes, CNPs are adept at operating within complex biological environments; depending on the type of cell membrane utilized, the resulting biomimetic nanoformulation is conferred with several properties typically associated with the source cell, including improved biocompatibility, immune evasion and tumour targeting. In …

A biohybrid nanoparticle formulation effectively treats rheumatoid arthritis by concurrently providing symptom relief and restoring proper immune function.

The interest in using therapeutic nanoparticles to bind with harmful molecules or pathogens and subsequently neutralize their bioactivity has grown tremendously. Among various nanomedicine platforms, cell membrane-coated nanoparticles, namely, “cellular nanosponges,” stand out for their broad-spectrum neutralization capability challenging to achieve in traditional countermeasure technologies. Such ability is attributable to their cellular function-based rather than target structure-based working principle. Integrating cellular nanosponges with various synthetic substrates further makes their applications exceptionally versatile and adaptive. This review discusses the latest cellular nanosponge technology focusing on how the structure–function relationship in different designs has led to versatile and potent medical countermeasures. Four design strategies are discussed, including harnessing native cell membrane …

While vaccines have been highly successful in protecting against various infections, there are still many high‐priority pathogens for which there are no clinically approved formulations. To overcome this challenge, researchers have explored the use of nanoparticulate strategies for more effective antigen delivery to the immune system. Along these lines, nanotoxoids are a promising biomimetic platform that leverages cell membrane coating technology to safely deliver otherwise toxic bacterial antigens in their native form for antivirulence vaccination. Here, in order to further boost their immunogenicity, nanotoxoids formulated against staphylococcal α‐hemolysin are embedded into a DNA‐based hydrogel with immunostimulatory CpG motifs. The resulting nanoparticle–hydrogel composite is injectable and improves the in vivo delivery of vaccine antigens while simultaneously stimulating nearby immune cells. This …

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 …

Botulinum toxin (BoNT) is a potent neurotoxin that poses a significant threat as a biowarfare weapon and a potential bioterrorist tool. Currently, there is a lack of effective countermeasures to combat BoNT intoxication in the event of a biological attack. Here, we report on a novel solution by combining cell metabolic engineering with cell membrane coating nanotechnology, resulting in the development of glycan-modified cellular nanosponges that serve as a biomimetic and broad-spectrum BoNT detoxification strategy. Specifically, we increase the expression levels of gangliosides on THP-1 cells through metabolic engineering, and then collect the modified THP-1 cell membrane and coat it onto synthetic polymeric cores, creating cellular nanosponges that closely mimic host cells. Our findings demonstrate that higher levels of gangliosides on the cellular nanosponges result in greater binding capacities with BoNT …

A large-scale screening identifies an inhalable polymer nanoparticle formulation that safely and effectively delivers therapeutic mRNA molecules to the lungs of several animal species.

Malaria infected erythrocytes utilize the parasite protein VAR2CSA to bind to a unique presentation of chondroitin sulfate (CS) for their placenta specific tropism. Interestingly, many cancers express a similar form of CS, thereby termed oncofetal CS (ofCS). The distinctive tropism of malaria infected erythrocytes and the identification of oncofetal CS, therefore, represent potentially potent tools for cancer targeting. Here we describe an intriguing drug delivery platform that effectively mimics infected erythrocytes and their specificity for ofCS. We used a lipid catcher-tag conjugation system for the functionalization of erythrocyte membrane-coated drug carriers with recombinant VAR2CSA (rVAR2). We show that these malaria mimicking erythrocyte nanoparticles (MMENPs) loaded with docetaxel (DTX) specifically target and kill melanoma cells in vitro. We further demonstrate effective targeting and therapeutic efficacy in a …

Robotic pills leverage the advantages of oral pharmaceutical formulations—in particular, convenient encapsulation, high loading capacity, ease of manufacturing and high patient compliance—as well as the multifunctionality, increasing miniaturization and sophistication of microrobotic systems. In this Perspective, we provide an overview of major innovations in the development of robotic pills—specifically, oral pills embedded with robotic capabilities based on microneedles, microinjectors, microstirrers or microrockets—summarize current progress and applicational gaps of the technology, and discuss its prospects. We argue that the integration of multiple microrobotic functions within oral delivery systems alongside accurate control of the release characteristics of their payload provides a basis for realizing sophisticated multifunctional robotic pills that operate as closed-loop systems.

Phototherapy is an emerging approach for cancer treatment that is effective at controlling the growth of primary tumors. In the presence of light irradiation, photothermal and photodynamic agents that are delivered to tumor sites can induce local hyperthermia and the production of reactive oxygen species, respectively, that directly eradicate cancer cells. Nanoparticles, characterized by their small size and tunable physiochemical properties, have been widely utilized as carriers for phototherapeutic agents to improve their biocompatibility and tumor‐targeted delivery. Nanocarriers can also be used to implement various codelivery strategies for further enhancing phototherapeutic efficiency. More recently, there has been considerable interest in augmenting the immunological effects of nanoparticle‐based phototherapies, which can yield durable and systemic antitumor responses. This review provides an overview of …

The highly multidrug‐resistant (MDR) Gram‐negative bacterial pathogen Acinetobacter baumannii is a top global health priority where an effective vaccine can protect susceptible populations and limit resistance acquisition. Outer membrane vesicles (OMVs) shed from Gram‐negative bacteria are enriched with virulence factors and membrane lipids but heterogeneous in size and cargo. Herein, a vaccine platform combining precise and replicable nanoparticle technology with immunogenic A. baumannii OMVs (Ab‐OMVs) is reported. Gold nanoparticle cores coated with Ab‐OMVs (Ab‐NPs) induce robust IgG titers in rabbits that enhance human neutrophil opsonophagocytic killing and passively protect against lethal A. baumannii sepsis in mice. Active Ab‐NP immunization in mice protects against sepsis and pneumonia, accompanied by B cell recruitment to draining lymph nodes, activation of dendritic cell markers …

Electrical impulse generation and its conduction within cells or cellular networks are the cornerstone of electrophysiology. However, the advancement of the field is limited by sensing accuracy and the scalability of current recording technologies. Here we describe a scalable platform that enables accurate recording of transmembrane potentials in electrogenic cells. The platform employs a three-dimensional high-performance field-effect transistor array for minimally invasive cellular interfacing that produces faithful recordings, as validated by the gold standard patch clamp. Leveraging the high spatial and temporal resolutions of the field-effect transistors, we measured the intracellular signal conduction velocity of a cardiomyocyte to be 0.182 m s−1, which is about five times the intercellular velocity. We also demonstrate intracellular recordings in cardiac muscle tissue constructs and reveal the signal conduction …

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 …

The rational design and application of mRNA‐based medicine have recently yielded some key successes in the clinical management of human diseases. mRNA technology allows for the facile and direct production of proteins in vivo, thus circumventing the need for lengthy drug development cycles and complex production workflows. As such, mRNA formulations can significantly improve upon the biological therapies that have become commonplace in modern medicine. Despite its many advantages, mRNA is inherently fragile and has specific delivery requirements. Leveraging the engineering flexibility of nanobiotechnology, mRNA payloads can be incorporated into nanoformulations such that they do not invoke unwanted immune responses, are targeted to tissues of interest, and can be delivered to the cytosol, resulting in improved safety while enhancing bioactivity. With the rapidly evolving landscape of …

Neurotoxins attack and destruct the nervous system, which can cause serious health problems and security threats. Existing detoxification approaches, such as antibodies and small molecule antidotes, rely on neurotoxin’s molecular structure as design cues and require toxin-specific development for each type of toxins. However, the enormous diversity of neurotoxins makes such structure-based development of antitoxin particularly challenging and inefficient. Here, we report on the development and use of neuronal membrane-coated nanosponges (denoted “Neuron-NS”) as an effective approach to detoxifying neurotoxins. Specifically, Neuron-NS act as neuron decoys to lure neurotoxins, bind with and neutralize the toxins, and thus block them from attacking the host neuron cells. These nanosponges detoxify neurotoxins regardless of their molecular structures and therefore can overcome the challenge posed by …

Biological neutralization represents a general strategy that deploys therapeutic agents to bind with harmful molecules or infectious pathogens, block their bioactivity, and thus prevent them from causing the diseases. Here, a comprehensive review of using cell‐membrane‐coated nanoparticles, namely “cellular nanosponges,” as host decoys for a wide range of biological neutralization applications is provided. Compared to traditional neutralization strategies, the cellular nanosponges stand out by mimicking susceptible host cells rather than accommodating the structures of the causative agents for the design of therapeutics. As all pathological agents must interact with host cells for bioactivity, nanosponges bypass the diversity of these agents and create function‐driven and broad‐spectrum neutralization solutions. The review focuses on the recent progress of using this new nanomedicine platform for neutralization …

The present invention relates to prevention and/or treatment of infection by a platelet-targeting microbe in a subject. The present invention provides for methods, combinations and pharmaceutical compositions for preventing and/or treating (and/or related uses) infection by a platelet-targeting microbe in a subject, using, inter alia, an effective amount of a nanoparticle comprising a) an inner core comprising a non-cellular material, b) an outer surface comprising a cellular membrane derived from a platelet; and optionally c) an agent for preventing said infection, treating said infec tion, diagnosing said infection, prognosing said infection and/or monitoring prevention or treatment of said infection. Exemplary platelet-targeting infections include infections by a bacterium, a virus, a fungus and/or a parasite.

Conventional sandwich immunosensors rely on antibody recognition layers to selectively capture and detect target antigen analytes. However, the fabrication of these traditional affinity sensors is typically associated with lengthy and multistep surface modifications of electrodes and faces the challenge of nonspecific adsorption from complex sample matrices. Here, we report on a unique design of bioelectronic affinity sensors by using natural cell membranes as recognition layers for protein detection and prevention of biofouling. Specifically, we employ the human macrophage (MΦ) membrane together with the human red blood cell (RBC) membrane to coat electrochemical transducers through a one-step process. The natural protein receptors on the MΦ membrane are used to capture target antigens, while the RBC membrane effectively prevents nonspecific surface binding. In an attempt to detect tumor necrosis …

The present invention relates treatments of a toxin in a subject. The toxin at least partially effects its toxicity in the subject via binding to a target cell of the subject. The present invention provides for methods, combinations and pharmaceutical compositions for decreasing or neutralizing the effect of a toxin in a subject, using, inter alia, an effective amount of a nanoparticle comprising an inner core comprising a non-cellular material, and an outer surface comprising a cellular membrane derived from a source cell. Exemplary toxins include acetylcholinesterase (AChE) inhibitors such as organophosphate poisoning.

Bioinspired microrobots capable of actively moving in biological fluids have attracted considerable attention for biomedical applications because of their unique dynamic features that are otherwise difficult to achieve by their static counterparts. Here we use click chemistry to attach antibiotic-loaded neutrophil membrane-coated polymeric nanoparticles to natural microalgae, thus creating hybrid microrobots for the active delivery of antibiotics in the lungs in vivo. The microrobots show fast speed (>110 µm s−1) in simulated lung fluid and uniform distribution into deep lung tissues, low clearance by alveolar macrophages and superb tissue retention time (>2 days) after intratracheal administration to test animals. In a mouse model of acute Pseudomonas aeruginosa pneumonia, the microrobots effectively reduce bacterial burden and substantially lessen animal mortality, with negligible toxicity. Overall, these findings …

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 …

White blood cells (WBCs) are immune cells that play essential roles in critical diseases including cancers, infections, and inflammatory disorders. Their dynamic and diverse functions have inspired the development of WBC membrane‐coated nanoparticles (denoted “WBC‐NPs”), which are formed by fusing the plasma membranes of WBCs, such as macrophages, neutrophils, T cells, and natural killer cells, onto synthetic nanoparticle cores. Inheriting the entire source cell antigens, WBC‐NPs act as source cell decoys and simulate their broad biointerfacing properties with intriguing therapeutic potentials. Herein, the recent development and medical applications of WBC‐NPs focusing on four areas, including WBC‐NPs as carriers for drug delivery, as countermeasures for biological neutralization, as nanovaccines for immune modulation, and as tools for the isolation of circulating tumor cells and fundamental …

Metal‐organic‐framework nanoparticles (MOF NPs) have been increasingly used to encapsulate therapeutic enzymes for delivery. To better interface these MOF NPs with biological systems, researchers have coated them with natural cell membranes, enabling biomimicking properties suitable for innovative biomedical applications. Herein, we report that the enzymatic activity of cell‐membrane‐coated MOF NPs can be significantly enhanced by reducing membrane cholesterol content. We demonstrate such cholesterol‐enzymatic activity correlation using zeolitic imidazolate framework‐8 MOF NPs to encapsulate catalase, horseradish peroxidase, and organophosphate hydrolase, respectively. MOF NPs coated with membranes of human red blood cells or macrophages show similar outcomes, illustrating the broad applicability of this finding. The mechanistic investigation further reveals that reducing cholesterol …

A biomimetic oxygen delivery carrier is provided by employing natural cell membrane as a stabilizer for fluorocarbon nanoemulsions. The resulting formulation exhibits a high capacity for delivering oxygen and can be used to successfully resuscitate subjects in need due to for example hemorrhagic shock. This natural-synthetic platform can alleviate the impact of blood shortages in clinical settings among other uses.

The protozoan pathogen Giardia lamblia is an important worldwide cause of diarrheal disease and malabsorption. Infection is managed with antimicrobials, although drug resistance and treatment failures are a clinical challenge. Prior infection provides significant protection, yet a human vaccine has not been realized. Individual antigens can elicit partial protection in experimental models, but protection is weaker than after prior infection. Here, we developed a multivalent nanovaccine by coating membranes derived from the parasite onto uniform and stable polymeric nanoparticles loaded with a mucosal adjuvant. Intranasal immunization with the nanovaccine induced adaptive immunity and effectively protected mice from G. lamblia infection.

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 …

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 …

The use of micromotors for active drug delivery via oral administration has recently gained considerable interest. However, efficient motor-assisted delivery into the gastrointestinal (GI) tract remains challenging, owing to the short propulsion lifetime of currently used micromotor platforms. Here, we report on an efficient algae-based motor platform, which takes advantage of the fast and long-lasting swimming behavior of natural microalgae in intestinal fluid to prolong local retention within the GI tract. Fluorescent dye or cell membrane–coated nanoparticle functionalized algae motors were further embedded inside a pH-sensitive capsule to enhance delivery to the small intestines. In vitro, the algae motors displayed a constant motion behavior in simulated intestinal fluid after 12 hours of continuous operation. When orally administered in vivo into mice, the algae motors substantially improved GI distribution of the dye …

The function of robots in extreme environments is regarded as one of the major challenges facing robotics. Here, we demonstrate that acidophilic microalgae biomotors can maintain their swimming behavior over long periods of time in the harsh acidic environment of the stomach, thus enabling them to be applied for gastrointestinal (GI) delivery applications. The biomotors can also be functionalized with a wide range of cargos, ranging from small molecules to nanoparticles, without compromising their ability to self-propel under extreme conditions. Successful GI delivery of model payloads after oral administration of the acidophilic algae motors is confirmed using a murine model. By tuning the surface properties of cargos, it is possible to modulate their precise GI localization. Overall, our findings indicate that multifunctional acidophilic algae-based biomotors offer distinct advantages compared to traditional biohybrid …

There has been considerable interest in developing synthetic micromotors with biofunctional, versatile, and adaptive capabilities for biomedical applications. In this perspective, cell membrane‐functionalized micromotors emerge as an attractive platform. This new class of micromotors demonstrates enhanced propulsion and compelling performance in complex biological environments, making them suitable for various in vivo applications, including drug delivery, detoxification, immune modulation, and phototherapy. This article reviews various proof‐of‐concept studies based on different micromotor designs and cell membrane coatings in these areas. The review focuses on the motor structure and performance relationship and highlights how cell membrane functionalization overcomes the obstacles faced by traditional synthetic micromotors while imparting them with unique capabilities. Overall, the cell membrane …

Cancer vaccines are promising treatments to prevent relapse after chemotherapy in acute myeloid leukemia (AML) patients, particularly for those who cannot tolerate intensive consolidation therapies. Here, we report the development of an AML cell membrane-coated nanoparticle (AMCNP) vaccine platform, in which immune-stimulatory adjuvant-loaded nanoparticles are coated with leukemic cell membrane material. This AMCNP vaccination strategy stimulates leukemia-specific immune responses by co-delivering membrane-associated antigens along with adjuvants to antigen-presenting cells. To demonstrate that this AMCNP vaccine enhances leukemia-specific antigen presentation and T cell responses, we modified a murine AML cell line to express membrane-bound chicken ovalbumin as a model antigen. AMCNPs were efficiently acquired by antigen-presenting cells in vitro and in vivo and stimulated antigen …

The present invention relates to prevention and/or treatment of diseases or disorders associated with a damaged or leaky vasculature in a subject. The present invention provides for methods, combinations and pharmaceutical compositions for preventing and/or treating a disease or disorder associ ated with a damaged or leaky vasculature in a subject, using, inter alia, an effective amount of a nanoparticle comprising an inner core comprising a non-cellular material, an outer surface comprising a cellular membrane derived from a platelet; and optionally an agent for preventing, treating, diagnosing, or prognosing the disease or disorder and/or monitoring prevention or treatment of the disease or disor der. Exemplary diseases or disorders include hemorrhage (bleeding), cardiovascular diseases or disorders, diseases or disorders associated with narrowing of a blood vessel, tumors or cancers.

Acinetobacter baumannii is a leading cause of antibiotic-resistant nosocomial infections with high mortality rates, yet there is currently no clinically approved vaccine formulation. During the onset of A. baumannii infection, neutrophils are the primary responders and play a major role in resisting the pathogen. Here, we design a biomimetic nanotoxoid for antivirulence vaccination by using neutrophil membrane-coated nanoparticles to safely capture secreted A. baumannii factors. Vaccination with the nanotoxoid formulation rapidly mobilizes innate immune cells and promotes pathogen-specific adaptive immunity. In murine models of pneumonia, septicemia, and superficial wound infection, immunization with the nanovaccine offers significant protection, improving survival and reducing signs of acute inflammation. Lower bacterial burdens are observed in vaccinated animals regardless of the infection route. Altogether …

Vaccination is a modality that has been widely explored for the treatment of various diseases. To increase the potency of vaccine formulations, immunostimulatory adjuvants have been regularly exploited, and the stimulator of interferon genes (STING) signaling pathway has recently emerged as a remarkable therapeutic target. STING is an endogenous protein on the endoplasmic reticulum that is a downstream sensor to cytosolic DNA. Upon activation, STING initiates a series of intracellular signaling cascades that ultimately generate potent type I interferon-mediated immune responses. Both natural and synthetic agonists have been used to stimulate the STING pathway, but they are usually administered locally due to low bioavailability, instability, and difficulty in bypassing the plasma membrane. With excellent pharmacokinetic profiles and versatility, nanocarriers can address many of these challenges and …

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.

Majority of drugs are administered orally, yet their efficient absorption is often difficult to achieve, with a low dose fraction reaching the blood compartment. Here, a microstirring pill technology is reported with built‐in mixing capability for oral drug delivery that greatly enhances bioavailability of its therapeutic payload. Embedding microscopic stirrers into a pill matrix enables faster disintegration and dissolution, leading to improved release profiles of three widely used model drugs, aspirin, levodopa, and acetaminophen, without compromising their loading. Unlike recently developed drug‐carrying nanomotors, drug molecules are not associated with the microstirrers, and hence there is no limitation on the loading capacity. These embedded microstirrers are fabricated through the asymmetric coating of titanium dioxide thin film onto magnesium microparticles. In vitro tests illustrate that the embedded microstirrers lead …

Nanoparticles have been widely explored for vaccine applications based on their ability to elicit potent immune responses. Their advantages include protection of antigen payloads, improved in vivo distribution, enhanced cellular uptake, and codelivery with immunostimulatory adjuvants, among others. Of the various nanoparticulate platform technologies, cell membrane‐coated nanoparticles are an emerging class of nanocarrier that have been utilized for a wide range of biomedical applications. Here, the development and application of nanotoxoids as vaccines against infection are reviewed. Prepared by the complexation of toxins with cell membrane‐coated nanoparticles, nanotoxoids are able to safely deliver virulent proteins in their native conformation, thus generating strong and high avidity immune responses. The synthesis of nanotoxoids leverages the natural affinities of virulence factors with cell …

Coronavirus disease 2019 (COVID-19), caused by the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become the worst pandemic disease of the current millennium. To address this crisis, therapeutic nanoparticles, including inorganic nanoparticles, lipid nanoparticles, polymeric nanoparticles, virus-like nanoparticles, and cell membrane-coated nanoparticles, have all offered compelling antiviral strategies. This article reviews these strategies in three categories: (1) nanoparticle-enabled detection of SARS-CoV-2, (2) nanoparticle-based treatment for COVID-19, and (3) nanoparticle vaccines against SARS-CoV-2. We discuss how nanoparticles are tailor-made to biointerface with the host and the virus in each category. For each nanoparticle design, we highlight its structure–function relationship that enables effective antiviral activity. Overall, nanoparticles bring numerous new …

There has been significant interest in developing cell membrane-coated nanoparticles due to their unique abilities of biomimicry and biointerfacing. As the technology progresses, it becomes clear that the application of these nanoparticles can be drastically broadened if additional functions beyond those derived from the natural cell membranes can be integrated. Herein, we summarize the most recent advances in the functionalization of cell membrane-coated nanoparticles. In particular, we focus on emerging methods, including (1) lipid insertion, (2) membrane hybridization, (3) metabolic engineering, and (4) genetic modification. These approaches contribute diverse functions in a nondisruptive fashion while preserving the natural function of the cell membranes. They also improve on the multifunctional and multitasking ability of cell membrane-coated nanoparticles, making them more adaptive to the complexity of …

Methods, systems, and devices are disclosed for intracellular payload delivery by nanomotor structures. In some aspects, a nanomotor for intracellular payload delivery includes an asymmetric body having a concave cavity at one end of the nanowire body; a functionalization layer on an outer surface of the nanowire body; and a payload substance coupled to the nanomotor by the functionalization layer in a biologically active conformation, wherein the payload substance is attached to a portion of the functionalization layer or at least partially encapsulated within the functionalization layer, in which the nanomotor is operable to propel in a biological medium and into an intracellular region of a living cell to initiate an interaction of the biologically active payload substance with an intracellular constituent of the living cell.

Staphylococcus aureus (S. aureus) is a leading human pathogen capable of producing severe invasive infections such as bacteremia, sepsis, and endocarditis with high morbidity and mortality, exacerbated by the increasingly widespread antibiotic resistance exemplified by methicillin-resistant strains (MRSA). S. aureus pathogenesis is fueled by the secretion of toxins—such as the membrane-damaging pore-forming α-toxin, which have diverse cellular targets including the epithelium, endothelium, leukocytes, and platelets. Here, we examine the use of human platelet membrane-coated nanoparticles (PNPs) as a biomimetic decoy strategy to neutralize S. aureus toxins and preserve host cell defense functions. The PNPs blocked platelet damage induced by S. aureus secreted toxins, thereby supporting platelet activation and bactericidal activity. Likewise, the PNPs blocked macrophage damage induced by S …

Cellular binding and entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are mediated by its spike glycoprotein (S protein), which binds with not only the human angiotensin-converting enzyme 2 (ACE2) receptor but also glycosaminoglycans such as heparin. Cell membrane-coated nanoparticles (“cellular nanosponges”) mimic the host cells to attract and neutralize SARS-CoV-2 through natural cellular receptors, leading to a broad-spectrum antiviral strategy. Herein, we show that increasing surface heparin density on the cellular nanosponges can promote their inhibition against SARS-CoV-2. Specifically, cellular nanosponges are made with azido-expressing host cell membranes followed by conjugating heparin to the nanosponge surfaces. Cellular nanosponges with a higher heparin density have a larger binding capacity with viral S proteins and a significantly higher inhibition efficacy …

Intratumoral immunotherapy is an emerging modality for the treatment of solid tumors. Toll-like receptor (TLR) agonists have shown promise for eliciting immune responses, but systemic administration often results in the development of adverse side effects. Herein, we investigate whether localized delivery of the TLR agonist, resiquimod (R848), via platelet membrane-coated nanoparticles (PNP-R848) elicits antitumor responses. The membrane coating provides a means of enhancing interactions with the tumor microenvironment, thereby maximizing the activity of R848. Intratumoral administration of PNP-R848 strongly enhances local immune activation and leads to complete tumor regression in a colorectal tumor model, while providing protection against repeated tumor re-challenges. Moreover, treatment of an aggressive breast cancer model with intratumoral PNP-R848 delays tumor growth and inhibits lung …

The present invention provides for compositions comprising a polymeric hydrogel impregnated with a toxin-absorbing or binding nanoparticle. The present invention also provides for the use of the above compositions for decreasing or neutralizing the effect of a toxin, or for treating or preventing an infection by a microbe that produces a toxin, in a subject. The exemplary toxin is a biological toxin such as a viral, bacterial, fungal, plant or animal toxin.(52) US CI. CPC A61K 9/06 (2013.01); A61K 9/0019 (2013.01); A61K 9/1629 (2013.01);(Continued) 23 Claims, 9 Drawing Sheets

The coronavirus SARS-CoV-2 can survive in wastewater for several days with a potential risk of waterborne human transmission, hence posing challenges in containing the virus and reducing its spread. Herein, we report on an active biohybrid microrobot system that offers highly efficient capture and removal of target virus from various aquatic media. The algae-based microrobot is fabricated by using click chemistry to functionalize microalgae with angiotensin-converting enzyme 2 (ACE2) receptor against the SARS-CoV-2 spike protein. The resulting ACE2-algae-robot displays fast (>100 μm/s) and long-lasting (>24 h) self-propulsion in diverse aquatic media including drinking water and river water, obviating the need for external fuels. Such movement of the ACE2-algae-robot offers effective “on-the-fly” removal of SARS-CoV-2 spike proteins and SARS-CoV-2 pseudovirus. Specifically, the active biohybrid …

Nanoparticle-based therapeutics have the potential to change the paradigm of how we approach the diagnosis and treatment of human disease. Employing naturally derived cell membranes as a surface coating has created a powerful new approach by which nanoparticles can be functionalized towards a wide range of biomedical applications. By using membranes derived from different cell sources, the resulting nanoparticles inherit properties that can make them well-suited for a variety of tasks. In recent years, stimuli-responsive platforms with the ability to release payloads on demand have received increasing attention due to their improved delivery, reduced side effects, and precision targeting. Nanoformulations have been developed to respond to external stimuli such as magnetic fields, ultrasound, and radiation, as well as local stimuli such as pH gradients, redox potentials, and other chemical conditions. Here …

Trichomonas vaginalis causes the most common, nonviral sexually transmitted infection. Only metronidazole (Mz) and tinidazole are approved for treating trichomoniasis, yet resistance is a clinical problem. The gold(I) complex, auranofin, is active against T. vaginalis and other protozoa but has significant human toxicity. In a systematic structure–activity exploration, we show here that diversification of gold(I) complexes, particularly as halides with simple C1–C3 trialkyl phosphines or as bistrialkyl phosphine complexes, can markedly improve potency against T. vaginalis and selectivity over human cells compared to that of the existing antirheumatic gold(I) drugs. All gold(I) complexes inhibited the two most abundant isoforms of the presumed target enzyme, thioredoxin reductase, but a subset of compounds were markedly more active against live T. vaginalis than the enzyme, suggesting that alternative targets exist …

Natural cell membranes derived from various cell sources have been successfully utilized to coat nanomaterials for functionalization. However, intracellular membranes from the organelles of eukaryotes remain unexplored. Herein, we choose mitochondrion as a representative cell organelle and coat outer mitochondrial membrane (OMM) from mouse livers onto nanoparticles and field-effect transistors (FETs) through a membrane vesicle–substrate fusion process. Polymeric nanoparticles coated with OMM (OMM-NPs) can bind with ABT-263, a B-cell lymphoma protein 2 (Bcl-2) inhibitor that targets the OMM. As a result, OMM-NPs effectively protect the cells from ABT-263 induced cell death and apoptosis in vitro and attenuated ABT-263-induced thrombocytopenia in vivo. Meanwhile, FET sensors coated with OMM (OMM-FETs) can detect and distinguish anti-Bcl-2 antibody and small molecule agonists. Overall …

Acute pancreatitis is a disease associated with suffering and high lethality. Although the disease mechanism is unclear, phospholipase A2 (PLA2) produced by pancreatic acinar cells is a known pathogenic trigger. Here, we show macrophage membrane-coated nanoparticles with a built-in ‘lure and kill’ mechanism (denoted ‘MΦ-NP(L&K)’) for the treatment of acute pancreatitis. MΦ-NP(L&K) are made with polymeric cores wrapped with natural macrophage membrane doped with melittin and MJ-33. The membrane incorporated melittin and MJ-33 function as a PLA2 attractant and a PLA2 inhibitor, respectively. These molecules, together with membrane lipids, work synergistically to lure and kill PLA2 enzymes. These nanoparticles can neutralize PLA2 activity in the sera of mice and human patients with acute pancreatitis in a dose-dependent manner and suppress PLA2-induced inflammatory response accordingly …

A nanoparticle comprising an outer surface comprising a plasma membrane derived from a cell that can be infected with a respiratory virus, including a human lung epithelial cell expressing ACE-2 receptor. Methods of manufacture and use for preventing or treating viral infections, such as coronavirus infection in a subject in need are disclosed.

The present invention relates to viral or cellular membrane coated nanostructures. Nanostructure networks, nanoscaf folds and articles of manufacture comprising the nanostruc ture, and uses thereof, are also provided. The present inven tion also relates to methods for anchoring, attaching and/or growing a target cell. Target cells, constituent (s) of the target cells, target substances made by the target cells or culture medium of the target cells prepared by the present methods, and uses thereof, are also provided.

The continued emergence of novel viruses poses a significant threat to global health. Uncontrolled outbreaks can result in pandemics that have the potential to overburden our healthcare and economic systems. While vaccination is a conventional modality that can be employed to promote herd immunity, antiviral vaccines can only be applied prophylactically and do little to help patients who have already contracted viral infections. During the early stages of a disease outbreak when vaccines are unavailable, therapeutic antiviral drugs can be used as a stopgap solution. However, these treatments do not always work against emerging viral strains and can be accompanied by adverse effects that sometimes outweigh the benefits. Nanotechnology has the potential to overcome many of the challenges facing current antiviral therapies. For example, nanodelivery vehicles can be employed to drastically improve the …

As numerous diseases are associated with increased local inflammation, directing drugs to the inflamed sites can be a powerful therapeutic strategy. One of the common characteristics of inflamed endothelial cells is the up-regulation of vascular cell adhesion molecule–1 (VCAM-1). Here, the specific affinity between very late antigen–4 (VLA-4) and VCAM-1 is exploited to produce a biomimetic nanoparticle formulation capable of targeting inflammation. The plasma membrane from cells genetically modified to constitutively express VLA-4 is coated onto polymeric nanoparticle cores, and the resulting cell membrane–coated nanoparticles exhibit enhanced affinity to target cells that overexpress VCAM-1 in vitro. A model anti-inflammatory drug, dexamethasone, is encapsulated into the nanoformulation, enabling improved delivery of the payload to inflamed lungs and significant therapeutic efficacy in vivo. Overall, this …

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 …

The combination of immunotherapy with other forms of treatment is an emerging strategy for boosting antitumor responses. By combining multiple modes of action, these combinatorial therapies can improve clinical outcomes through unique synergisms. Here, a microrobot‐based strategy that integrates tumor tissue disruption with biological stimulation is shown for cancer immunotherapy. The microrobot is fabricated by loading bacterial outer membrane vesicles onto a self‐propelling micromotor, which can react with water to generate a propulsion force. When administered intratumorally to a solid tumor, the disruption of the local tumor tissue coupled with the delivery of an immunostimulatory payload leads to complete tumor regression. Additionally, treatment of the primary tumor results in the simultaneous education of the host immune system, enabling it to control the growth of distant tumors. Overall, this work …

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 …

The rapid emergence of antibiotic resistance is recognized as a major public health threat. Nanomaterials have risen to tackle this problem through either improving the potency of existing antibiotics or generating entirely new antibacterial mechanisms.

The incorporation of nanoparticles into hydrogels yields novel superstructures that have become increasingly popular in biomedical research. Each component of these nanoparticle–hydrogel superstructures can be easily modified, resulting in platforms that are highly tunable and inherently multifunctional. The advantages of the nanoparticle and hydrogel constituents can be synergistically combined, enabling these superstructures to excel in scenarios where employing each component separately may have suboptimal outcomes. In this review, the synthesis and fabrication of different nanoparticle–hydrogel superstructures are discussed, followed by an overview of their use in a range of applications, including drug delivery, detoxification, immune modulation, and tissue engineering. Overall, these platforms hold significant clinical potential, and it is envisioned that future development along these lines will lead to …

Small interfering RNA (siRNA) is a powerful tool for gene silencing that has been used for a wide range of biomedical applications, but there are many challenges facing its therapeutic use in vivo. Here, we report on a platelet cell membrane–coated metal-organic framework (MOF) nanodelivery platform for the targeted delivery of siRNA in vivo. The MOF core is capable of high loading yields, and its pH sensitivity enables endosomal disruption upon cellular uptake. The cell membrane coating provides a natural means of biointerfacing with disease substrates. It is shown that high silencing efficiency can be achieved in vitro against multiple target genes. Using a murine xenograft model, significant antitumor targeting and therapeutic efficacy are observed. Overall, the biomimetic nanodelivery system presented here provides an effective means of achieving gene silencing in vivo and could be used to expand the …

Inflammatory cytokines are key players in modulating immune responses to mount effective host defense. However, excessive production of inflammatory cytokines contributes to the destructive components responsible for various inflammatory disorders. As a result, treatment strategies have been developed to lower the cytokine levels or block their bioactivity. In particular, therapeutic agents that directly capture and neutralize cytokines have gained significant attention as they bypass the interactions with the host cells, and therefore, are less likely to induce immunogenic response and clearance. Among them, “monoplex” platforms such as cytokine-neutralizing antibodies (CNAs) are commonly designed to target a specific cytokine for neutralization. Meanwhile, to address the multiplexity of the cytokine targets in diseases, multiplex platforms such as glycosaminoglycan-containing biomaterials and cell-membrane …

NanoEngineering and Chemical Engineering Program at the University of California, San Diego. 1 Founded in 2007, NanoEngineering is the newest of six departments in the Jacobs School of Engineering. It comprises 26 research-active professors and a contingent of four teaching professors, whose area of focus is the core undergraduate curriculum in chemical engineering. The research interests of the department are highly interdisciplinary it is known internationally for its strengths in nanomedicine, flexible electronics, and energy storage, with broad areas of overlap. A particular strength of the department that cuts across all research areas is computational materials science. This interdisciplinarity is, in part, a product of the diversity of the educational backgrounds of the faculty; most of us have undergraduate training in chemical engineering, chemistry, or materials science (approximately equally represented …

Background Compared to proteins, glycans, and lipids, much less is known about RNAs on the cell surface. We develop a series of technologies to test for any nuclear-encoded RNAs that are stably attached to the cell surface and exposed to the extracellular space, hereafter called membrane-associated extracellular RNAs (maxRNAs). Results We develop a technique called Surface-seq to selectively sequence maxRNAs and validate two Surface-seq identified maxRNAs by RNA fluorescence in situ hybridization. To test for cell-type specificity of maxRNA, we use antisense oligos to hybridize to single-stranded transcripts exposed on the surface of human peripheral blood mononuclear cells (PBMCs). Combining this strategy with imaging flow cytometry, single-cell RNA sequencing, and maxRNA sequencing, we identify monocytes as the major type of maxRNA+ PBMCs and prioritize 11 candidate maxRNAs for …

Synthetic nanoparticles coated with cellular membranes have been increasingly explored to harness natural cell functions toward the development of novel therapeutic strategies. Herein, we report on a unique bacterial membrane-coated nanoparticle system as a new and exciting antibacterial vaccine. Using Escherichia coli as a model pathogen, we collect bacterial outer membrane vesicles (OMVs) and successfully coat them onto small gold nanoparticles (AuNPs) with a diameter of 30 nm. The resulting bacterial membrane-coated AuNPs (BM-AuNPs) show markedly enhanced stability in biological buffer solutions. When injected subcutaneously, the BM-AuNPs induce rapid activation and maturation of dendritic cells in the lymph nodes of the vaccinated mice. In addition, vaccination with BM-AuNPs generates antibody responses that are durable and of higher avidity than those elicited by OMVs only. The BM …

A tubular micromotor with spatially resolved compartments is presented toward efficient site‐specific cargo delivery, with a back‐end zinc (Zn) propellant engine segment and an upfront cargo‐loaded gelatin segment further protected by a pH‐responsive cap. The multicompartment micromotors display strong gastric‐powered propulsion with tunable lifetime depending on the Zn segment length. Such propulsion significantly enhances the motor distribution and retention in the gastric tissues, by pushing and impinging the front‐end cargo segment onto the stomach wall. Once the micromotor penetrates the gastric mucosa (pH ≥ 6.0), its pH‐responsive cap dissolves, promoting the autonomous localized cargo release. The fabrication process, physicochemical properties, and propulsion behavior are systematically tested and discussed. Using a mouse model, the multicompartment motors, loaded with a model cargo …

The recent success of immunotherapies has highlighted the power of leveraging the immune system in the fight against cancer. In order for most immune‐based therapies to succeed, T cell subsets with the correct tumor‐targeting specificities must be mobilized. When such specificities are lacking, providing the immune system with tumor antigen material for processing and presentation is a common strategy for stimulating antigen‐specific T cell populations. While straightforward in principle, experience has shown that manipulation of the antigen presentation process can be incredibly complex, necessitating sophisticated strategies that are difficult to translate. Herein, the design of a biomimetic nanoparticle platform is reported that can be used to directly stimulate T cells without the need for professional antigen‐presenting cells. The nanoparticles are fabricated using a cell membrane coating derived from cancer …

Therapeutic strategies that provide effective and broad‐spectrum neutralization against HIV-1 infection are highly desirable. Here, we investigate the potential of nanoengineered CD4+ T cell membrane-coated nanoparticles (TNP) to neutralize a broad range of HIV-1 strains. TNP displayed outstanding neutralizing breadth and potency; they neutralized all 125 HIV-1-pseudotyped viruses tested, including global subtypes/recombinant forms, and transmitted/founder viruses, with a geometric mean 80% inhibitory concentration (IC80) of 819 μg ml−1 (range, 72 to 8,570 μg ml−1). TNP also selectively bound to and induced autophagy in HIV-1-infected CD4+ T cells and macrophages, while having no effect on uninfected cells. This TNP-mediated autophagy inhibited viral release and reduced cell-associated HIV-1 in a dose- and phospholipase D1-dependent manner. Genetic or pharmacological inhibition of …

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 …

Living cells, such as red blood cells (RBCs) modified with functional micromotors with the aid of ultrasound propulsion and magnetic guidance. Iron oxide nanoparticles are loaded into the RBCs, where their asymmetric distribution within the cells results in a net magnetization, thus enabling magnetic alignment and guidance under acoustic propulsion. The RBC motors display efficient guided and prolonged propulsion in various biological fluids, including undiluted whole blood.

Inhibition of phospholipase A2 (PLA2) has long been considered for treating various diseases associated with an elevated PLA2 activity. However, safe and effective PLA2 inhibitors remain unavailable. Herein, we report a biomimetic nanoparticle design that enables a “lure and kill” mechanism designed for PLA2 inhibition (denoted “L&K‐NP”). The L&K‐NPs are made of polymeric cores wrapped with modified red blood cell membrane with two inserted key components: melittin and oleyloxyethyl phosphorylcholine (OOPC). Melittin acts as a PLA2 attractant that works together with the membrane lipids to “lure” in‐coming PLA2 for attack. Meanwhile, OOPC acts as inhibitor that “kills” PLA2 upon enzymatic attack. Both compounds are integrated into the L&K‐NP structure, which voids toxicity associated with free molecules. In the study, L&K‐NPs effectively inhibit PLA2‐induced hemolysis. In mice administered with a …

Platelets exhibit distinct surface moieties responsible for modulating their adhesion to various disease‐relevant substrates involving vascular damage, immune evasion, and pathogen interactions. Such broad biointerfacing capabilities of platelets have inspired the development of platelet‐mimicking drug carriers that preferentially target drug payloads to disease sites for enhanced therapeutic efficacy. Among these carriers, platelet membrane–coated nanoparticles (denoted “PNPs”) made by cloaking synthetic substrates with the plasma membrane of platelets have emerged recently. Their “top‐down” design combines the functionalities of natural platelet membrane and the engineering flexibility of synthetic nanomaterials, which together create synergy for effective drug delivery and novel therapeutics. Herein, the recent progress of engineering PNPs with different structures for targeted drug delivery is reviewed …

Therapeutic enzymes used for genetic disorders or metabolic diseases oftentimes suffer from suboptimal pharmacokinetics and stability. Nanodelivery systems have shown considerable promise for improving the performance of enzyme therapies. Here, we develop a cell membrane-camouflaged metal–organic framework (MOF) system with enhanced biocompatibility and functionality. The MOF core can efficiently encapsulate enzymes while maintaining their bioactivity. After the introduction of natural cell membrane coatings, the resulting nanoformulations can be safely administered in vivo. The surface receptors on the membrane can also provide additional functionalities that synergize with the encapsulated enzyme to target disease pathology from multiple dimensions. Employing uricase as a model enzyme, we demonstrate the utility of this approach in multiple animal disease models. The results support the …

We report cellular nanosponges as an effective medical countermeasure to the SARS-CoV-2 virus. Two types of cellular nanosponges are made of the plasma membranes derived from human lung epithelial type II cells or human macrophages. These nanosponges display the same protein receptors, both identified and unidentified, required by SARS-CoV-2 for cellular entry. It is shown that, following incubation with the nanosponges, SARS-CoV-2 is neutralized and unable to infect cells. Crucially, the nanosponge platform is agnostic to viral mutations and potentially viral species, as well. As long as the target of the virus remains the identified host cell, the nanosponges will be able to neutralize the virus.

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 …

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 …

Transforming natural cells into functional biocompatible robots capable of active movement is expected to enhance the functions of the cells and revolutionize the development of synthetic micromotors. However, present cell-based micromotor systems commonly require the propulsion capabilities of rigid motors, external fields, or harsh conditions, which may compromise biocompatibility and require complex actuation equipment. Here, we report on an endogenous enzyme-powered Janus platelet micromotor (JPL-motor) system prepared by immobilizing urease asymmetrically onto the surface of natural platelet cells. This Janus distribution of urease on platelet cells enables uneven decomposition of urea in biofluids to generate enhanced chemophoretic motion. The cell surface engineering with urease has negligible impact on the functional surface proteins of platelets, and hence, the resulting JPL-motors …