Transferrin Receptor-Targeted Aptamer-Drug Conjugate Overcomes Blood-Brain Barrier for Potent Glioblastoma Therapy.

Glioblastoma (GBM) is the leading primary malignant tumor in the central nervous system. Current clinical therapeutics for treating GBM patients yield limited benefits. However, the development of new therapeutic methods is hindered because the blood-brain barrier (BBB) restricts drug penetration.

Lipid Nanoparticles-Mediated mRNA Delivery to the Eye Affected by Ionizable Cationic Lipid.

Ionizable lipid serves as the key functional component in lipid nanoparticles (LNPs) for efficient mRNA delivery. This study aims to systematically evaluate clinically approved ionizable lipid DLin-MC3-DMA and SM102-based LNPs for ocular mRNA delivery, with a comprehensive assessment of their physicochemical characteristics, delivery efficiency, and biodistribution patterns within the ocular microenvironment. Enhanced green fluorescence protein or Luc encoding mRNA-loaded LNPs were formulated using microfluidic mixing technology and characterized by dynamic light scattering, ζ-potential measurements, and cryogenic transmission electron microscopy imaging.

Sortilin-Mediated Rapid, Precise and Sustained Degradation of Membrane Proteins via mRNA-Encoded Lysosome-Targeting Chimera.

Recent advances in lysosome-targeting degradation technologies have introduced strategies to regulate therapeutic membrane proteins (MPs), potentially transforming treatment paradigms. However, challenges persist, including limited degradation precision due to the broad distribution of lysosome-targeting receptors (LTRs), as well as the high cost and complexity of recombinant protein production or chemical synthesis. Herein, it identifies sortilin as a promising LTR, highly expressed in malignancies but minimally present in healthy tissues outside the nervous system.

mRNA-Based Cancer Vaccines: Advancements and Prospects.

The success of mRNA COVID-19 vaccines has reinvigorated research and interest in mRNA-based cancer vaccines. Despite promising results in clinical trials, therapeutic mRNA-based cancer vaccines have not yet been approved for human use. These vaccines are designed to trigger tumor regression, establish enduring antitumor memory, and mitigate adverse reactions.

A DNA Molecular Logic Circuit for Precise Tumor Identification.

Tumor-associated antigens (TAAs) are not exclusively expressed in cancer cells, inevitably causing the "on target, off tumor" effect of molecular recognition tools. To achieve precise recognition of cancer cells, by using protein tyrosine kinase 7 (PTK7) as a model TAA, a DNA molecular logic circuit Aisgc8 was rationally developed by arranging H-binding i-motif, ATP-binding aptamer, and PTK7-targeting aptamer Sgc8c in a DNA sequence. Aisgc8 output the conformation of Sgc8c to recognize PTK7 on cells in a simulated tumor microenvironment characterized by weak acidity and abundant ATP, but not in a simulated physiological environment.

Phase Separation of DNA-Encoded Artificial Cells Boosts Signal Amplification for Biosensing.

Life-like hierarchical architecture shows great potential for advancing intelligent biosensing, but modular expansion of its sensitivity and functionality remains a challenge. Drawing inspiration from intracellular liquid-liquid phase separation, we discovered that a DNA-encoded artificial cell with a liquid core (LAC) can enhance peroxidase-like activity of Hemin and its DNA G-quadruplex aptamer complex (DGAH) without substrate-selectivity, unlike its gelled core (GAC) counterpart. The LAC is easily engineered as an ultrasensitive biosensing system, benefiting from DNA's high programmability and unique signal amplification capability mediated by liquid-liquid phase separation.

An Aptamer-Functionalized DNA Circuit to Establish an Artificial Interaction between T Cells and Cancer Cells.

Nongenetic strategies that enable control over the cell-cell interaction network would be highly desired, particularly in T cell-based cancer immunotherapy. In this work, we developed an aptamer-functionalized DNA circuit to modulate the interaction between T cells and cancer cells. This DNA circuit was composed of recognition-then-triggering and aggregation-then-activation modules.

Programming Affinity for Precise Tumor Recognition with Allosteric Nanosensing-Circles.

Although many smart probes for precise tumor recognition have been reported, the challenge of "on-target, off-tumor" remains. Therefore, we herein report the fabrication of a series of allosterically tunable DNA nanosensing-circles (NSCs). The recognition affinity of NSCs is programmed through sensitivity to tumor microenvironment (TME) hallmarks such as small molecules, acidity, or oncoproteins.

Aptamer-based expansion microscopy platform enables signal-amplified imaging of dendritic spines.

Super-resolution imaging of dendritic spines (DS) can provide valuable information for mechanistic studies related to synaptic physiology and neural plasticity, but challenged by their small dimension (50-200 nm) below the spatial resolution of conventional optical microscopes. In this work, by combining the molecular recognition specificity of aptamer with high programmability of DNA nanotechnology, we developed an expansion microscopy (ExM) platform for imaging DS with enhanced spatial resolution and amplified signal output. Our results demonstrated that the aptamer probe could specifically bind to DS of primary hippocampal neurons.

Bioinspired molecular engineering of bivalent aptamers by ligand-induced self-dimerization.

A bioinspired "point-and-shoot" molecular strategy is described for engineering noncovalent aptamers K-induced reassembly of a split G-quadruplex sequence at the end of monomeric aptamers. This design compensates for insufficient cell recognition of monovalent aptamers in biological environments and minimizes structure-induced nonspecific cell binding, expending the aptamer toolbox available for complex systems.

Aptamer-Based Targeted Delivery of Functional Nucleic Acids.

Functional nucleic acid (NA)-based drugs have a broad range of applications since they allow the alteration and control of gene/protein expression patterns in cells. In principle, functional NAs need to be transported precisely and efficiently to target cells to guarantee both functionality and safety. Owing to their negative charges, it is difficult for natural NAs to cross the cell membrane composed of lipid bilayer and enter targeted cells.

Aptamer-Based Targeted Protein Degradation.

The selective removal of misfolded, aggregated, or aberrantly overexpressed protein plays an essential role in maintaining protein-dominated biological processes. In parallel, the precise knockout of abnormal proteins is inseparable from the accurate identification of proteins within complex environments. Guided by these precepts, small molecules, or antibodies, are commonly used as protein recognition tools for developing targeted protein degradation (TPD) technology.

X-Ray-triggered Carbon Monoxide and Manganese Dioxide Generation based on Scintillating Nanoparticles for Cascade Cancer Radiosensitization.

Carbon monoxide (CO) is an endogenous signaling molecule with broad therapeutic effects. Here, a multifunctional X-ray-triggered carbon monoxide (CO) and manganese dioxide (MnO ) generation nanoplatform based on metal carbonyl and scintillating nanoparticles (SCNPs) is reported. Attributed to the radioluminescent characteristic of SCNPs, UV-responsive Mn (CO) is not only indirectly activated to release CO by X-ray but can also be degraded into MnO .

Molecular elements: novel approaches for molecular building.

Classically, a molecular element (ME) is a pure substance composed of two or more atoms of the same element. However, MEs, in the context of this review, can be any molecules as elements bonded together into the backbone of synthetic oligonucleotides (ONs) with designed sequences and functions, including natural A, T, C, G, U, and unnatural bases. The use of MEs can facilitate the synthesis of designer molecules and smart materials.

Artificial Nucleotide Aptamer-Based Field-Effect Transistor for Ultrasensitive Detection of Hepatoma Exosomes.

An aptamer-based field-effect transistor (Apta-FET) is a well-developed assay method with high selectivity and sensitivity. Due to the limited information density that natural nucleotide library holds, the Apta-FET faces fundamental restriction in universality to detect various types of analytes. Herein, we demonstrate a type of Apta-FET sensors based on an artificial nucleotide aptamer (AN-Apta-FET).

Bispecific Aptamer-Based Recognition-then-Conjugation Strategy for PD1/PDL1 Axis Blockade and Enhanced Immunotherapy.

Cytotoxic T cells initiate antitumor effects mainly through direct interactions with tumor cells. As a counter to this, tumor cells can put the brakes on such T-cell activity via specific linkage between programmed death ligand 1 (PDL1) and its receptor programmed cell death protein 1 (PD1). Bispecific inhibitors that enabled synchronous blockade of PD1 and PDL1, thereby releasing the brakes on T-cell antitumor activity, should significantly improve the efficacy of immune checkpoint blockade (ICB) therapy.

A pH-Responsive Covalent Nanoscale Device Enhancing Temporal and Force Stability for Specific Tumor Imaging.

Approaches to DNA probe-mediated precision medicine have been extensively explored for the diagnosis and treatment of diverse types of cancer. Despite this, simple nanoscale devices with the required recognition specificity and sensitivity for clinical application have remained elusive until now. Here, we report a pH-driven covalent nanoscale device that integrates pH-responsive, switchable structure and proximity-driven covalent cross-linking.

Oral antibiotics relieve allergic asthma in post-weaning mice reducing iNKT cells and function of ADRB2.

The role of normal gut microbiota in asthma or ovalbumin (OVA)-induced asthma tolerance (OT) remains unclear. Here, we established mouse models of asthma and OT followed by 2 weeks of antibiotic treatment, to clear the gut microbiota. Antibiotic treatment was found to alleviate allergic asthma accompanied with a reduction of invariant natural killer (iNKT) cells.

Aptamer-Functionalized Nanodevices for Dynamic Manipulation of Membrane Receptor Signaling in Living Cells.

The capacity to regulate the signaling amplitude of membrane receptors in a user-defined manner would open various opportunities for precise biological study and therapy. While partial agonists enabled downtuning of cellular responses, they required esoteric optimization of the ligand-receptor interface, limiting their practical applications. Herein, we developed an aptamer-functionalized, tweezer-like nanodevice to dynamically modulate the cellular behavior through control over the distance between receptors in the dimer with no need to involve complicated structural analysis.

Engineering Aptamers with Selectively Enhanced Biostability in the Tumor Microenvironment.

Aptamers are emerging as promising molecular tools in cancer-targeted theranostics. Improving their in vivo stability has been a critical issue in promoting clinical translation, but such efforts could lead to more serious side effects resulting from prolonged retention in healthy organs. To address this problem, we developed an environment-responsive stabilization strategy for the selective enhancement of aptamer biostability in the tumor microenvironment (TME).

Aptasensors for Cancerous Exosome Detection.

Cancerous exosomes that carry multiple biomarkers are attractive targets for the early diagnosis and therapy of cancer. As one of the powerful molecular recognition tools, aptamers with excellent binding affinity and specificity toward biomarkers have been exploited to construct various aptamer-based biosensors (aptasensors) for exosome detection. Here, we review recent advances in aptasensors for the detection of cancerous exosomes.

Functional Aptamer-Embedded Nanomaterials for Diagnostics and Therapeutics.

In the past decades, various nanomaterials with unique properties have been explored for bioapplications. Meanwhile, aptamers, generated from the systematic evolution of ligands by exponential enrichment technology, are becoming an indispensable element in the design of functional nanomaterials because of their small size, high stability, and convenient modification, especially endowing nanomaterials with recognition capability to specific targets. Therefore, the incorporation of aptamers into nanomaterials offers an unprecedented opportunity in the research fields of diagnostics and therapeutics.

Decoding the Complex Free Radical Cascade by Using a DNA Framework-Based Artificial DNA Encoder.

DNA-based molecular communications (DMC) are critical for regulating biological networks to maintain stable organismic functions. However, the complicated, time-consuming information transmission process involved in genome-coded DMC and the limited, vulnerable decoding activity generally lead to communication impairment or failure, in response to external stimuli. Herein, we present a conceptually innovative DMC strategy mediated by the DNA framework-based artificial DNA encoder.

Transducing Complex Biomolecular Interactions by Temperature-Output Artificial DNA Signaling Networks.

The requirement of special expensive instruments for quantitative information readout has significantly restricted sustainable development, from ideation to execution, of advanced artificial networks. Here we present a step toward a paradigm of evolutionary signaling networks that enable translating complex signaling information into easy-to-read temperature output. Combining DNA molecular engineering with basic optical mechanisms, a DNA/Hemin complex-derived versatile temperature-output transducer is established, which can be coupled with other functional modules to fabricate diverse portable DNA signaling networks by dynamic programming of DNA chemical reactions.