Targeted Sub-Attomole Cancer Biomarker Detection Based on Phase Singularity 2D Nanomaterial-Enhanced Plasmonic Biosensor

Detection of small cancer biomarkers with low molecular weight and a low concentration range has always been challenging yet urgent in many clinical applications such as diagnosing early-stage cancer,monitoring treatment and detecting relapse.Here,a highly enhanced plasmonic biosensor that can overcome this challenge is developed using atomically thin two-dimensional phase change nanomaterial.By precisely engineering the configuration with atomically thin materials,the phase singularity has been successfully achieved with a significantly enhanced lateral position shift effect.Based on our knowledge,it is the first experimental demonstration of a lateral position signal change>340μm at a sensing interface from all optical techniques.With this enhanced plasmonic effect,the detection limit has been experimentally demonstrated to be 10^(-15) mol L^(−1) for TNF-α cancer marker,which has been found in various human diseases including inflammatory diseases and different kinds of cancer.The as-reported novel integration of atomically thin Ge_(2)Sb_(2)Te_(5) with plasmonic substrate, which results in a phase singularity and thus a giant lateral position shift, enables the detection of cancer markers with low molecular weight at femtomolar level. These results will definitely hold promising potential in biomedical application and clinical diagnostics.

Label-free biosensing with singular-phaseenhanced lateral position shift based on atomically thin plasmonic nanomaterials

Rapid plasmonic biosensing has attracted wide attention in early disease diagnosis and molecular biology research.However,it was still challenging for conventional angle-interrogating plasmonic sensors to obtain higher sensitivity without secondary amplifying labels such as plasmonic nanoparticles.To address this issue,we developed a plasmonic biosensor based on the enhanced lateral position shift by phase singularity.Such singularity presents as a sudden phase retardation at the dark point of reflection from resonating plasmonic substrate,leading to a giant position shift on reflected beam.Herein,for the first time,the atomically thin layer of Ge2Sb2Te5(GST)on silver nanofilm was demonstrated as a novel phase-response-enhancing plasmonic material.The GST layer was not only precisely engineered to singularize phase change but also served as a protective layer for active silver nanofilm.This new configuration has achieved a record-breaking largest position shift of 439.3μm measured in calibration experiments with an ultra-high sensitivity of 1.72×10^(8)nm RIU−1(refractive index unit).The detection limit was determined to be 6.97×10^(−7)RIU with a 0.12μm position resolution.Besides,a large figure of merit(FOM)of 4.54×10^(11)μm(RIU∙°)^(−1)was evaluated for such position shift interrogation,enabling the labelfree detection of trace amounts of biomolecules.In targeted biosensing experiments,the optimized sensor has successfully detected small cytokine biomarkers(TNF-αand IL-6)with the lowest concentration of 1×10^(−16)M.These two molecules are the key proinflammatory cancer markers in clinical diagnosis,which cannot be directly screened by current clinical techniques.To further validate the selectivity of our sensing systems,we also measured the affinity of integrin binding to arginylglycylaspartic acid(RGD)peptide(a key protein interaction in cell adhesion)with different Mn2+ion concentrations,ranging from 1 nM to 1 mM.

RSPSSL:A novel high-fidelity Raman spectral preprocessing scheme to enhance biomedical applications and chemical resolution visualization

Raman spectroscopy has tremendous potential for material analysis with its molecular fingerprinting capability in many branches of science and technology.It is also an emerging omics technique for metabolic profiling to shape precision medicine.However,precisely attributing vibration peaks coupled with specific environmental,instrumental,and specimen noise is problematic.Intelligent Raman spectral preprocessing to remove statistical bias noise and sample-related errors should provide a powerful tool for valuable information extraction.Here,we propose a novel Raman spectral preprocessing scheme based on self-supervised learning(RSPSSL)with high capacity and spectral fidelity.It can preprocess arbitrary Raman spectra without further training at a speed of~1900 spectra per second without human interference.The experimental data preprocessing trial demonstrated its excellent capacity and signal fidelity with an 88%reduction in root mean square error and a 60%reduction in infinite norm(L__(∞))compared to established techniques.With this advantage,it remarkably enhanced various biomedical applications with a 400%accuracy elevation(ΔAUC)in cancer diagnosis,an average 38%(few-shot)and 242%accuracy improvement in paraquat concentration prediction,and unsealed the chemical resolution of biomedical hyperspectral images,especially in the spectral fingerprint region.It precisely preprocessed various Raman spectra from different spectroscopy devices,laboratories,and diverse applications.This scheme will enable biomedical mechanism screening with the label-free volumetric molecular imaging tool on organism and disease metabolomics profiling with a scenario of high throughput,cross-device,various analyte complexity,and diverse applications.

Low-temperature optothermal nanotweezers

Optical tweezers that rely on laser irradiation to capture and manipulate nanoparticles have provided powerful tools for biological and biochemistry studies.However,the existence of optical diffraction-limit and the thermal damage caused by high laser power hinder the wider application of optical tweezers in the biological field.For the past decade,the emergence of optothermal tweezers has solved the above problems to a certain extent,while the auxiliary agents used in optothermal tweezers still limit their biocompatibility.Here,we report a kind of nanotweezers based on the sign transformation of the thermophoresis coefficient of colloidal particles in low-temperature environment.Using a self-made microfluidic refrigerator to reduce the ambient temperature to around 0℃in the microfluidic cell,we can control a single nanoparticle at lower laser power without adding additional agent solute in the solution.This novel optical tweezering scheme has provided a new path for the manipulation of inorganic nanoparticles as well as biological particles.

CRISPR-powered optothermal nanotweezers:Diverse bio-nanoparticle manipulation and single nucleotide identification

Optothermal nanotweezers have emerged as an innovative optical manipulation technique in the past decade,which revolutionized classical optical manipulation by efficiently capturing a broader range of nanoparticles.However,the optothermal temperature field was merely employed for in-situ manipulation of nanoparticles,its potential for identifying bio-nanoparticles remains largely untapped.Hence,based on the synergistic effect of optothermal manipulation and CRIPSR-based bio-detection,we developed CRISPR-powered optothermal nanotweezers(CRONT).Specifically,by harnessing diffusiophoresis and thermo-osmotic flows near the substrate upon optothermal excitation,we successfully trapped and enriched DNA functionalized gold nanoparticles,CRISPR-associated proteins,as well as DNA strands.Remarkably,we built an optothermal scheme for enhancing CRISPR-based single-nucleotide polymorphism(SNP)detection at single molecule level,while also introducing a novel CRISPR methodology for observing nucleotide cleavage.Therefore,this innovative approach has endowed optical tweezers with DNA identification ability in aqueous solution which was unattainable before.With its high specificity and feasibility for in-situ bio-nanoparticle manipulation and identification,CRONT will become a universal tool in point-of-care diagnosis,biophotonics,and bio-nanotechnology.

Passively and actively enhanced surface plasmon resonance sensing strategies towards single molecular detection

Surface plasmonic resonance(SPR)has been a corner stone for approaching single molecular detection due to its highsensitivity capability and simple detection mechanism,and has brought major advancements in biomedicine and life science technology.Over decades,the successful integration of SPR with versatile techniques has been demonstrated.However,several crucial limitations have hindered this technique for practical applications,such as long detection time and low overall sensitivity.This review aims to provide a comprehensive summary of existing approaches in enhancing the performance of SPR sensors based on“passive”and“active”methods.Firstly,passive enhancement is discussed from a material aspect,including signal amplification tags and modifications of conventional substrates.Then,the focus is on the most popular active enhancement methods including electrokinetic,optical,magnetic,and acoustic manipulations that are summarized with highlights on their advantageous features and ability to concentrate target molecules at the detection sites.Lastly,prospects and future development directions for developing SPR sensing towards a more practical,single molecular detection technique in the next generation are discussed.This review hopes to inspire researchers’interests in developing SPR-related technology with more innovative and influential ideas.

Advances in inorganic nanoparticles trapping stiffness measurement:A promising tool for energy and environmental study

Optical tweezers system has emerged as an efficient tool to manipulate tiny particles in a non-invasive way.Trapping stiffness,as an essential parameter of an optical potential well,represents the trapping stability.Additionally,trapping inorganic nanoparticles such as metallic nanoparticles or other functionalized inorganic nanoparticles is important due to their properties of good stability,high conductivity,tolerable toxicity,etc.,which makes it an ideal detection strategy for bio-sensing,force calculation,and determination of particle and environmental properties.However,the trapping stiffness measurement(TSM)methods of inorganic nanoparticles have rarely been analyzed and summarized.Here,in this review,the principle and methods of TSM are analyzed.We also systematically summarize the progress in acquiring inorganic particles trapping stiffness and its promising applications.In addition,we provide prospects of the energy and environment applications of optical tweezering technique and TSM.Finally,the challenges and future directions of achieving the nanoparticles trapping stiffness are discussed.