Dual-Modal Cellular Nanoparticles for Continuous Neurotoxin Detoxification.

Neurotoxins are known for their extreme lethality. However, due to their enormous diversity, effective and broad-spectrum countermeasures are lacking. This study presents a dual-modal cellular nanoparticle (CNP) formulation engineered for continuous neurotoxin neutralization. The formulation involves encapsulating the metabolic enzyme N-sulfotransferase (SxtN) into metal-organic framework (MOF) nanoparticle cores and coating them with a natural neuronal membrane, termed "Neuron-MOF/SxtN-NPs". The resulting nanoparticles combine membrane-enabled broad-spectrum neurotoxin neutralization with enzyme payload-enabled continuous neurotoxin neutralization. The studies confirm the protection of the enzyme payload by the MOF core and validate the continuous neutralization of saxitoxin (STX). In vivo studies conducted using a mouse model of STX intoxication reveal markedly improved survival rates compared with control groups. Furthermore, acute toxicity assessments show no adverse effects associated with the administration of Neuron-MOF/SxtN-NPs in healthy mice. Overall, Neuron-MOF/SxtN-NPs represent a unique biomimetic nanomedicine platform poised to effectively neutralize neurotoxins, marking an important advancement in the field of countermeasure nanomedicine.

Protein-Loaded Cellular Nanosponges for Dual-Biomimicry Neurotoxin Countermeasure.

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 within the nanoparticle core. The comprehensive in vitro assays, including cell osmotic swelling, calcium flux, and cytotoxicity assays, demonstrate the improved detoxification efficacy of Neuron-MOF/Sxph-NS. Furthermore, in mouse models of STX intoxication, the application of Neuron-MOF/Sxph-NS shows significant survival benefits in both therapeutic and prophylactic regimens, without any apparent acute toxicity. Overall, the development of Neuron-MOF/Sxph-NS represents an important advancement in neurotoxin detoxification, offering promising potential for treating injuries and diseases caused by neurotoxins and addressing the current limitations in neurotoxin countermeasures.

Design Strategies for Cellular Nanosponges as Medical Countermeasures.

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 functions for biological neutralization, functionalizing cell membrane coatings to enhance neutralization capabilities, combining cell membranes and functional cores for multimodal neutralization, and integrating cellular nanosponges with hydrogels for localized applications. Examples in each design strategy are selected, and the discussion is to highlight their structure-function relationships in complex disease settings. The review may inspire additional design strategies for cellular nanosponges and fulfill even broader medical applications.

Designs of metal-organic framework nanoparticles for protein delivery.

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 also discussed. Overall, this review will promote designs of MOF-NPs with unique properties to address unmet medical needs.

Emerging nanoparticle designs against bacterial infections.

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 door to nontraditional antibacterial nanomedicines that rely on mechano-bactericidal, function-driven, nature-inspired, or virulence-targeting mechanisms to overcome antibiotic resistance for more effective antibacterial therapy. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease.

DNA Origami Disguises Herpes Simplex Virus 1 Particles and Controls Their Virulence.

DNA nanostructures are well-established vectors for packaging diversified payloads for targeted cellular delivery. Here, DNA origami rectangular sheets were combined with Herpes Simplex Virus 1 (HSV1) capsids to demonstrate surface coverage of the particle via electrostatic interactions. The optimized origami:HSV1 molar ratios led to characteristic packaging geometries ranging from dispersed "HSV1 pockets" to agglomerated "HSV1 sleeves". "Pockets" were disguised from cells in HeLa and B16F10 cells and were 44.2% less infective than naked HSV1 particles. However, the pockets were 117% more infective than naked HSV1 particles when the origami sheets were coated with folic acid. We observed infectivity from naked origami, but they are 99.1% less infective with respect to HSV1 and 99.6% less infective with respect to the pocket complexes. This work suggests that DNA origami can selectively modulate virus infectivity.

Membrane Cholesterol Depletion Enhances Enzymatic Activity of Cell-Membrane-Coated Metal-Organic-Framework Nanoparticles.

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 levels effectively enhances membrane permeability likely responsible for the increased enzymatic activity. These results also imply a facile approach to tailoring the enzymatic activity of cell-membrane-coated MOF NPs by simply tuning the membrane cholesterol level.

Bioderived DNA Nanomachines for Potential Uses in Biosensing, Diagnostics, and Therapeutic Applications.

Beside its genomic properties, DNA is also recognized as a novel material in the field of nanoengineering. The specific bonding of base pairs can be used to direct the assembly of highly structured materials with specific nanoscale features such as periodic 2D arrays, 3D nanostructures, assembly of nanomaterials, and DNA nanomachines. In recent years, a variety of DNA nanomachines are developed because of their many potential applications in biosensing, diagnostics, and therapeutic applications. In this review, the fuel-powered motors and secondary structure motors, whose working mechanisms are inspired or derived from natural phenomena and nanomachines, are discussed. The combination of DNA motors with other platforms is then discussed. In each section of these motors, their mechanisms and their usage in the biomedical field are described. Finally, it is believed that these DNA-based nanomachines and hybrid motifs will become an integral point-of-care diagnostics and smart, site-specific therapeutic delivery.

Versatile DNA Origami Nanostructures in Simplified and Modular Designing Framework.

We introduce a simplified and modular architecture for design and construction of complex origami nanostructures. A series of basic two-dimensional and three-dimensional structures are presented. As the resulting structures can be virtually divided into blocks, modular remodeling such as translocation, contraction/extension, and bending is carried out. Structures under such a designing framework are morphable. Local conformational changes can propagate to the entire structure to reshape the global conformation.

A common set of distinct features that characterize noncoding RNAs across multiple species.

To find signature features shared by various ncRNA sub-types and characterize novel ncRNAs, we have developed a method, RNAfeature, to investigate >600 sets of genomic and epigenomic data with various evolutionary and biophysical scores. RNAfeature utilizes a fine-tuned intra-species wrapper algorithm that is followed by a novel feature selection strategy across species. It considers long distance effect of certain features (e.g. histone modification at the promoter region). We finally narrow down on 10 informative features (including sequences, structures, expression profiles and epigenetic signals). These features are complementary to each other and as a whole can accurately distinguish canonical ncRNAs from CDSs and UTRs (accuracies: >92% in human, mouse, worm and fly). Moreover, the feature pattern is conserved across multiple species. For instance, the supervised 10-feature model derived from animal species can predict ncRNAs in Arabidopsis (accuracy: 82%). Subsequently, we integrate the 10 features to define a set of noncoding potential scores, which can identify, evaluate and characterize novel noncoding RNAs. The score covers all transcribed regions (including unconserved ncRNAs), without requiring assembly of the full-length transcripts. Importantly, the noncoding potential allows us to identify and characterize potential functional domains with feature patterns similar to canonical ncRNAs (e.g. tRNA, snRNA, miRNA, etc) on ∼70% of human long ncRNAs (lncRNAs).