Configurable phonon polaritons in twisted α-MoO3.

Moiré engineering is being intensively investigated as a method to tune the electronic, magnetic and optical properties of twisted van der Waals materials. Advances in moiré engineering stem from the formation of peculiar moiré superlattices at small, specific twist angles. Here we report configurable nanoscale light-matter waves-phonon polaritons-by twisting stacked α-phase molybdenum trioxide (α-MoO3) slabs over a broad range of twist angles from 0° to 90°. Our combined experimental and theoretical results reveal a variety of polariton wavefront geometries and topological transitions as a function of the twist angle. In contrast to the origin of the modified electronic band structure in moiré superlattices, the polariton twisting configuration is attributed to the electromagnetic interaction of highly anisotropic hyperbolic polaritons in stacked α-MoO3 slabs. These results indicate twisted α-MoO3 to be a promising platform for nanophotonic devices with tunable functionalities.

Author Correction: Configurable phonon polaritons in twisted α-MoO3.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Calligraphy of Nanoplasmonic Bioink-Based Multiplex Immunosensor for Precision Immune Monitoring and Modulation.

Immunomodulation therapies have attracted immense interest recently for the treatment of immune-related diseases, such as cancer and viral infections. This new wave of enthusiasm for immunomodulators, predominantly revolving around cytokines, has spurred emerging needs and opportunities for novel immune monitoring and diagnostic tools. Considering the highly dynamic immune status and limited window for therapeutic intervention, precise real-time detection of cytokines is critical to effectively monitor and manage the immune system and optimize the therapeutic outcome. The clinical success of such a rapid, sensitive, multiplex immunoanalytical platform further requires the system to have ease of integration and fabrication for sample sparing and large-scale production toward massive parallel analysis. In this article, we developed a nanoplasmonic bioink-based, label-free, multiplex immunosensor that can be readily "written" onto a glass substrate via one-step calligraphy patterning. This facile nanolithography technique allows programmable patterning of a minimum of 3 µL of nanoplasmonic bioink in 1 min and thus enables fabrication of a nanoplasmonic microarray immunosensor with 2 h simple incubation. The developed immunosensor was successfully applied for real-time, parallel detection of multiple cytokines (e.g., interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-ß)) in immunomodulated macrophage samples. This integrated platform synergistically incorporates the concepts of nanosynthesis, nanofabrication, and nanobiosensing, showing great potential in the scalable production of label-free multiplex immunosensing devices with superior analytical performance for clinical applications in immunodiagnostics and immunotherapy.

Enhanced Label-Free Nanoplasmonic Cytokine Detection in SARS-CoV-2 Induced Inflammation Using Rationally Designed Peptide Aptamer.

Rapid and precise serum cytokine quantification provides immense clinical significance in monitoring the immune status of patients in rapidly evolving infectious/inflammatory disorders, examplified by the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. However, real-time information on predictive cytokine biomarkers to guide targetable immune pathways in pathogenic inflammation is critically lacking, because of the insufficient detection range and detection limit in current label-free cytokine immunoassays. In this work, we report a highly sensitive localized surface plasmon resonance imaging (LSPRi) immunoassay for label-free Interleukin 6 (IL-6) detection utilizing rationally designed peptide aptamers as the capture interface. Benefiting from its characteristically smaller dimension and direct functionalization on the sensing surface via Au-S bonding, the peptide-aptamer-based LSPRi immunoassay achieved enhanced label-free serum IL-6 detection with a record-breaking limit of detection down to 4.6 pg/mL, and a wide dynamic range of ∼6 orders of magnitude (values from 4.6 to 1 × 106 pg/mL were observed). The immunoassay was validated in vitro for label-free analysis of SARS-CoV-2 induced inflammation, and further applied in rapid quantification of serum IL-6 profiles in COVID-19 patients. Our peptide aptamer LSPRi immunoassay demonstrates great potency in label-free cytokine detection with unprecedented sensing capability to provide accurate and timely interpretation of the inflammatory status and disease progression, and determination of prognosis.

Modeling Protein Aggregation Kinetics: The Method of Second Stochasticization.

The nucleation of protein aggregates and their growth are important in determining the structure of the cell's membraneless organelles as well as the pathogenesis of many diseases. The large number of molecular types of such aggregates along with the intrinsically stochastic nature of aggregation challenges our theoretical and computational abilities. Kinetic Monte Carlo simulation using the Gillespie algorithm is a powerful tool for modeling stochastic kinetics, but it is computationally demanding when a large number of diverse species is involved. To explore the mechanisms and statistics of aggregation more efficiently, we introduce a new approach to model stochastic aggregation kinetics which introduces noise into already statistically averaged equations obtained using mathematical moment closure schemes. Stochastic moment equations summarize succinctly the dynamics of the large diversity of species with different molecularity involved in aggregation but still take into account the stochastic fluctuations that accompany not only primary and secondary nucleation but also aggregate elongation, dissociation, and fragmentation. This method of "second stochasticization" works well where the fluctuations are modest in magnitude as is often encountered in vivo where the number of protein copies in some computations can be in the hundreds to thousands. Simulations using second stochasticization reveal a scaling law that correlates the size of the fluctuations in aggregate size and number with the total number of monomers. This scaling law is confirmed using experimental data. We believe second stochasticization schemes will prove valuable for bridging the gap between in vivo cell biology and detailed modeling. (The code is released on https://github.com/MYTLab/stoch-agg.).

Machine-Learning-Assisted Microfluidic Nanoplasmonic Digital Immunoassay for Cytokine Storm Profiling in COVID-19 Patients.

Cytokine storm, known as an exaggerated hyperactive immune response characterized by elevated release of cytokines, has been described as a feature associated with life-threatening complications in COVID-19 patients. A critical evaluation of a cytokine storm and its mechanistic linkage to COVID-19 requires innovative immunoassay technology capable of rapid, sensitive, selective detection of multiple cytokines across a wide dynamic range at high-throughput. In this study, we report a machine-learning-assisted microfluidic nanoplasmonic digital immunoassay to meet the rising demand for cytokine storm monitoring in COVID-19 patients. Specifically, the assay was carried out using a facile one-step sandwich immunoassay format with three notable features: (i) a microfluidic microarray patterning technique for high-throughput, multiantibody-arrayed biosensing chip fabrication; (ii) an ultrasensitive nanoplasmonic digital imaging technology utilizing 100 nm silver nanocubes (AgNCs) for signal transduction; (iii) a rapid and accurate machine-learning-based image processing method for digital signal analysis. The developed immunoassay allows simultaneous detection of six cytokines in a single run with wide working ranges of 1-10,000 pg mL-1 and ultralow detection limits down to 0.46-1.36 pg mL-1 using a minimum of 3 µL serum samples. The whole chip can afford a 6-plex assay of 8 different samples with 6 repeats in each sample for a total of 288 sensing spots in less than 100 min. The image processing method enhanced by convolutional neural network (CNN) dramatically shortens the processing time ∼6,000 fold with a much simpler procedure while maintaining high statistical accuracy compared to the conventional manual counting approach. The immunoassay was validated by the gold-standard enzyme-linked immunosorbent assay (ELISA) and utilized for serum cytokine profiling of COVID-19 positive patients. Our results demonstrate the nanoplasmonic digital immunoassay as a promising practical tool for comprehensive characterization of cytokine storm in patients that holds great promise as an intelligent immunoassay for next generation immune monitoring.

Nanoplasmonic Sandwich Immunoassay for Tumor-Derived Exosome Detection and Exosomal PD-L1 Profiling.

Tumor-derived exosomes play a vital role in the process of cancer development. Quantitative analysis of exosomes and exosome-shuttled proteins would be of immense value in understanding cancer progression and generating reliable predictive biomarkers for cancer diagnosis and treatment. Recent studies have indicated the critical role of exosomal programmed death ligand 1 (PD-L1) in immune checkpoint therapy and its application as a patient stratification biomarker in cancer immunotherapy. Here, we present a nanoplasmonic exosome immunoassay utilizing gold-silver (Au@Ag) core-shell nanobipyramids and gold nanorods, which form sandwich immune complexes with target exosomes. The immunoassay generates a distinct plasmonic signal pattern unique to exosomes with specific exosomal PD-L1 expression, allowing rapid, highly sensitive exosome detection and accurate identification of PD-L1 exosome subtypes in a single assay. The developed nanoplasmonic sandwich immunoassay provides a novel and viable approach for tumor cell-derived exosome detection and analysis with quantitative molecular details of key exosomal proteins, manifesting its great potential as a transformative diagnostic tool for early cancer detection, prognosis, and post-treatment monitoring.

Phonon Polaritons in Monolayers of Hexagonal Boron Nitride.

Phonon polaritons in van der Waals materials reveal significant confinement accompanied with long propagation length: important virtues for tasks pertaining to the control of light and energy flow at the nanoscale. While previous studies of phonon polaritons have relied on relatively thick samples, here reported is the first observation of surface phonon polaritons in single atomic layers and bilayers of hexagonal boron nitride (hBN). Using antenna-based near-field microscopy, propagating surface phonon polaritons in mono- and bilayer hBN microcrystals are imaged. Phonon polaritons in monolayer hBN are confined in a volume about one million times smaller than the free-space photons. Both the polariton dispersion and their wavelength-thickness scaling law are altered compared to those of hBN bulk counterparts. These changes are attributed to phonon hardening in monolayer-thick crystals. The data reported here have bearing on applications of polaritons in metasurfaces and ultrathin optical elements.