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Abstract Optical metasurfaces, consisting of subwavelength‐scale meta‐atom arrays, hold great promise of overcoming the fundamental limitations of conventional optics. Due to their structural complexity, metasurfaces usually require high‐resolution yet slow and expensive fabrication processes. Here, using a metasurface polarimetric imaging device as an example, the photonic structures and the Nanoimprint lithography (NIL) processes are designed, creating two separate NIL molds over a patterning area of > 20 mm²with designed Moiré alignment markers by electron‐beam writing, and further subsequently integrate silicon and aluminum metasurface structures on a chip. Uniquely, the silicon and aluminum metasurfaces are fabricated by using the nanolithography and 3D pattern‐transfer capabilities of NIL, respectively, achieving nanometer‐scale linewidth uniformity, sub‐200 nm translational overlay accuracy, and <0.017 rotational alignment error while significantly reducing fabrication complexity and surface roughness. The micro‐sized multilayer metasurfaces have high circular polarization extinction ratios as large as ≈20 and ≈80 in blue and red wavelengths. Further, the metasurface chip‐integrated CMOS imager demonstrates high accuracy in broad‐band, full Stokes parameter analysis in the visible wavelength ranges and single‐shot polarimetric imaging. This novel, NIL‐based, multilayered nanomanufacturing approach is applicable to the scalable production of large‐area functional structures for ultra‐compact optic, electronic, and quantum devices. 

The measurement of neutralizing immune responses to viral infection is essential, given the heterogeneity of human immunity and the emergence of new virus strains. However, neutralizing antibody (nAb) assays often require high-level biosafety containment, sophisticated instrumentation, and long detection times. Here, as a proof-of-principle, we designed a nanoparticle-supported, rapid, electronic detection (NasRED) assay to assess the neutralizing potency of monoclonal antibodies (mAbs) against SARS-CoV-2. The gold nanoparticles (AuNPs) coated with human angiotensin-converting enzyme 2 (ACE2) protein as nAb potency reporters were mixed with the mAbs to be tested, as well as streptavidin-conjugated multivalent spike (S) protein or their receptor binding domains (RBD). High-affinity and ACE2-competitive nAbs alter the S (or RBD)-to-ACE2 binding level and modulate AuNP cluster formation and precipitation. The amount of free-floating AuNP reporters is quantified by a semiconductor-based readout system that measures the AuNPs' optical extinction, producing nAb signals that can differentiate SARS-CoV-2 variants (Wuhan-Hu-1, Gamma, and Omicron). The modular design nature, short assay time (less than 30 minutes), and portable and inexpensive readout system make this NasRED-nAb assay applicable to measuring vaccine potency, immune responses to infection, and the efficacy of antibody-based therapies. 

Major challenges remain to precisely detect low-abundance proteins rapidly and cost-effectively from diverse biofluids. Here we present a gold nanoparticle (AuNP)-supported, rapid electronic detection (NasRED) platform with sub-femtomolar sensitivity and high specificity. Surface-functionalized AuNPs act as multivalent detectors to recognize target antigens and antibodies through high-affinity binding, subsequently forming aggregates precipitated in a microcentrifuge tube and producing a solution color change. The residual floating AuNPs’ optical extinction is digitized using customized circuitry incorporating inexpensive optoelectronics and feedback mechanisms for stabilized readout. NasRED introduces active fluidic forces through engineered centrifugation and vortex agitation, effectively promoting low-concentration protein detection and accelerating signal transduction. Using SARS-CoV-2 as a demonstration, NasRED enables detection of both antibodies and antigens from a small sample volume (6 µL), distinguishes the viral antigens from those of human coronaviruses, and delivers test results in <15 min. The limits of detection (LoDs) for antibody detection are approximately 49 aM (7 fg/mL) in phosphate-buffered saline (PBS), or >3,000 times more sensitive than Enzyme-Linked Immunosorbent Assay (ELISA), ~76 aM (11 fg/mL) in human pooled serum and in the femtomolar range in diluted whole blood. For nucleocapsid protein detection, NasRED LoDs are ~190 aM (10 fg/mL) in human saliva and ~2 fM (100 fg/mL) in nasal fluid. Unlike centralized platforms, NasRED is a one-pot, in-solution assay without the needs for washing, labeling, expensive instrumentation or highly trained operators. With low reagent costs and a compact system footprint, this modular digital platform is well-suited for accurate, near-patient diagnosis and screening of a wide range of infectious and chronic diseases. 

Thrombospondin-2 (THBS2) is a prevailing prognostic biomarker implicated in different cancer types, such as deadly colorectal, pancreas, and triple-negative breast cancers. While the current methods for cancer-relevant protein detection, such as enzyme-linked immunosorbent assay (ELISA), mass spectrometry, and immunohistochemistry, are feasible at advanced stages, they have shortcomings in sensitivity, specificity, and accessibility, particularly at low concentrations in complex biological fluids for early detection. Here, we propose and demonstrate a modular, in-solution assay design concept, Nanoparticle-Supported Rapid Electronic Detection (NasRED), as a versatile cancer screening and diagnostic platform. NasRED utilizes antibody-functionalized gold nanoparticles (AuNPs) to capture target proteins from a minute amount of sample (<10 µL) and achieve optimal performance with a short assay time by introducing active fluidic forces that act to promote biochemical reaction and accelerate signal transduction. This rapid (15 min) process serves to form AuNP clusters upon THBS2 binding and subsequently precipitate such clusters, resulting in color modulation of the test tubes that is dependent on the THBS2 concentration. Finally, a semiconductor-based, portable electronic device is used to digitize the optical signals for the sensitive detection of THBS2. High sensitivity (femtomolar level) and a large dynamic range (five orders of magnitude) are obtained to analyze THBS2 spiked in PBS, serum, whole blood, saliva, cerebrospinal fluids, and synovial fluids. High specificity is also preserved in differentiating THBS2 from other markers such as cancer antigen (CA) 19-9 and bovine serum albumin (BSA). This study highlights NasRED’s potential to enhance cancer prognosis and screening by offering a cost-effective, accessible, and minimally invasive solution. 

Simple and fast detection of small molecules is critical for health and environmental monitoring. Methods for chemical detection often use mass spectrometers or enzymes; the former relies on expensive equipment, and the latter is limited to those that can act as enzyme substrates. Affinity reagents like antibodies can target a variety of small-molecule analytes, but the detection requires the successful design of chemically conjugated targets or analogs for competitive binding assays. Here, we developed a generalizable method for the highly sensitive and specific in-solution detection of small molecules, using cannabidiol (CBD) as an example. Our sensing platform uses gold nanoparticles (AuNPs) functionalized with a pair of chemically induced dimerization (CID) nanobody binders (nanobinders), where CID triggers AuNP aggregation and sedimentation in the presence of CBD. Despite moderate binding affinities of the two nanobinders to CBD (equilibrium dissociation constants KD of ∼6 and ∼56 μM), a scheme consisting of CBD−AuNP preanalytical incubation, centrifugation, and electronic detection (ICED) was devised to demonstrate a high sensitivity (limit of detection of ∼100 picomolar) in urine and saliva, a relatively short sensing time (∼2 h), a large dynamic range (5 logs), and a sufficiently high specificity to differentiate CBD from its analog, tetrahydrocannabinol. The high sensing performance was achieved with the multivalency of AuNP sensing, the ICED scheme that increases analyte concentrations in a small assay volume, and a portable electronic detector. This sensing system is readily applicable for wide molecular diagnostic applications.