Circular Polarization-Resolved Raman Optical Activity: A Perspective on Chiral Spectroscopies of Vibrational States.

Circular polarization-resolved Raman scattering methods include Raman optical activity (ROA) and its derivative─surface-enhanced Raman optical activity (SEROA). These spectroscopic modalities are rapidly developing due to their high information content, stand-off capabilities, and rapid development of Raman-active chiral nanostructures. These methods enable a direct readout of the vibrational energy levels of chiral molecules, crystals, and nanostructured materials, making it possible to study complex interactions and the dynamic interfaces between them. They were shown to be particularly valuable for nano- and biotechnological fields encompassing complex particles with nanoscale chirality that combine strong scattering and intense polarization rotation. This perspective dives into recent advancements in ROA and SEROA, their distinction from surface-enhanced Raman scattering, and the potential of these information-rich label-free spectroscopies for the detection of chiral biomolecules.

3D Bioprinted Tumor-Stroma Models of Triple-Negative Breast Cancer Stem Cells for Preclinical Targeted Therapy Evaluation.

Breast cancer stem cells (CSCs) play a pivotal role in therapy resistance and tumor relapse, emphasizing the need for reliable in vitro models that recapitulate the complexity of the CSC tumor microenvironment to accelerate drug discovery. We present a bioprinted breast CSC tumor-stroma model incorporating triple-negative breast CSCs (TNB-CSCs) and stromal cells (human breast fibroblasts), within a breast-derived decellularized extracellular matrix bioink. Comparison of molecular signatures in this model with different clinical subtypes of bioprinted tumor-stroma models unveils a unique molecular profile for artificial CSC tumor models. We additionally demonstrate that the model can recapitulate the invasive potential of TNB-CSC. Surface-enhanced Raman scattering imaging allowed us to monitor the invasive potential of tumor cells in deep z-axis planes, thereby overcoming the depth-imaging limitations of confocal fluorescence microscopy. As a proof-of-concept application, we conducted high-throughput drug testing analysis to assess the efficacy of CSC-targeted therapy in combination with conventional chemotherapeutic compounds. The results highlight the usefulness of tumor-stroma models as a promising drug-screening platform, providing insights into therapeutic efficacy against CSC populations resistant to conventional therapies.

SERS in 3D cell models: a powerful tool in cancer research.

Unraveling the cellular and molecular mechanisms underlying tumoral processes is fundamental for the diagnosis and treatment of cancer. In this regard, three-dimensional (3D) cancer cell models more realistically mimic tumors compared to conventional 2D cell cultures and are more attractive for performing such studies. Nonetheless, the analysis of such architectures is challenging because most available techniques are destructive, resulting in the loss of biochemical information. On the contrary, surface-enhanced Raman spectroscopy (SERS) is a non-invasive analytical tool that can record the structural fingerprint of molecules present in complex biological environments. The implementation of SERS in 3D cancer models can be leveraged to track therapeutics, the production of cancer-related metabolites, different signaling and communication pathways, and to image the different cellular components and structural features. In this review, we highlight recent progress in the use of SERS for the evaluation of cancer diagnosis and therapy in 3D tumoral models. We outline strategies for the delivery and design of SERS tags and shed light on the possibilities this technique offers for studying different cellular processes, through either biosensing or bioimaging modalities. Finally, we address current challenges and future directions, such as overcoming the limitations of SERS and the need for the development of user-friendly and robust data analysis methods. Continued development of SERS 3D bioimaging and biosensing systems, techniques, and analytical strategies, can provide significant contributions for early disease detection, novel cancer therapies, and the realization of patient-tailored medicine.

A Scaffold-Assisted 3D Cancer Cell Model for Surface-Enhanced Raman Scattering-Based Real-Time Sensing and Imaging.

Despite recent advances in the development of scaffold-based three-dimensional (3D) cell models, challenges persist in imaging and monitoring cell behavior within these complex structures due to their heterogeneous cell distribution and geometries. Incorporating sensors into 3D scaffolds provides a potential solution for real-time, in situ sensing and imaging of biological processes such as cell growth and disease development. We introduce a 3D printed hydrogel-based scaffold capable of supporting both surface-enhanced Raman scattering (SERS) biosensing and imaging of 3D breast cancer cell models. The scaffold incorporates plasmonic nanoparticles and SERS tags, for sensing and imaging, respectively. We demonstrate the scaffold's adaptability and modularity in supporting breast cancer spheroids, thereby enabling spatial and temporal monitoring of tumor evolution.

High-Throughput Morphological Chirality Quantification of Twisted and Wrinkled Gold Nanorods.

Chirality in gold nanostructures offers an exciting opportunity to tune their differential optical response to left- and right-handed circularly polarized light, as well as their interactions with biomolecules and living matter. However, tuning and understanding such interactions demands quantification of the structural features that are responsible for the chiral behavior. Electron tomography (ET) enables structural characterization at the single-particle level and has been used to quantify the helicity of complex chiral nanorods. However, the technique is time-consuming and consequently lacks statistical value. To address this issue, we introduce herein a high-throughput methodology that combines images acquired by secondary electron-based electron beam-induced current (SEEBIC) with quantitative image analysis. As a result, the geometric chirality of hundreds of nanoparticles can be quantified in less than 1 h. When combining the drastic gain in data collection efficiency of SEEBIC with a limited number of ET data sets, a better understanding of how the chiral structure of individual chiral nanoparticles translates into the ensemble chiroptical response can be reached.

Single Crystal and Pentatwinned Gold Nanorods Result in Chiral Nanocrystals with Reverse Handedness.

Handedness is an essential attribute of chiral nanocrystals, having a major influence on their properties. During chemical growth, the handedness of nanocrystals is usually tuned by selecting the corresponding enantiomer of chiral molecules involved in asymmetric growth, often known as chiral inducers. We report that, even using the same chiral inducer enantiomer, the handedness of chiral gold nanocrystals can be reversed by using Au nanorod seeds with either single crystalline or pentatwinned structure. This effect holds for chiral growth induced both by amino acids and by chiral micelles. Although it was challenging to discern the morphological handedness for L-cystine-directed particles, even using electron tomography, both cases showed circular dichroism bands of opposite sign, with nearly mirrored chiroptical signatures for chiral micelle-directed growth, along with quasi-helical wrinkles of inverted handedness. These results expand the chiral growth toolbox with an effect that might be exploited to yield a host of interesting morphologies with tunable optical properties.

Nanocomposite hydrogel microneedles: a theranostic toolbox for personalized medicine.

Due to the severity and high prevalence of cancer, as well as its complex pathological condition, new strategies for cancer treatment and diagnostics are required. As such, it is important to design a toolbox that integrates multiple functions on a single smart platform. Theranostic hydrogels offer an innovative and personalized method to tackle cancer while also considering patient comfort, thereby facilitating future implementation and translation to the clinic. In terms of theranostic systems used in cancer therapy, nanoparticles are widely used as diagnostic and therapeutic tools. Nanoparticles can achieve systemic circulation, evade host defenses, and deliver drugs and signaling agents at the targeted site, to diagnose and treat the disease at a cellular and molecular level. In this context, hydrogel microneedles have a high potential for multifunctional operation in medical devices, while avoiding the complications associated with the systemic delivery of therapeutics. Compared with oral administration and subcutaneous injection, microneedles offer advantages such as better patient compliance, faster onset of action, and improved permeability and efficacy. In addition, they comprise highly biocompatible polymers with excellent degradability and tunable properties. Nanoparticles and microneedles thus offer the possibility to expand the theranostic potential through combined synergistic use of their respective features. We review herein recent advances concerning processing methods and material requirements within the realm of hydrogel microneedles as theranostic platforms, various approaches toward cancer therapy, and the incorporation of nanoparticles for added functionality.

Enhanced Photocurrent and Electrically Pumped Quantum Dot Emission from Single Plasmonic Nanoantennas.

Integrating cavity-enhanced colloidal quantum dots (QDs) into photonic chip devices would be transformative for advancing room-temperature optoelectronic and quantum photonic technologies. However, issues with efficiency, stability, and cost remain formidable challenges to reach the single antenna limit. Here, we present a bottom-up approach that delivers single QD-plasmonic nanoantennas with electrical addressability. These QD nanojunctions exhibit robust photoresponse characteristics, with plasmonically enhanced photocurrent spectra matching the QD solution absorption. We demonstrate electroluminescence from individual plasmonic nanoantennas, extending the device lifetime beyond 40 min by utilizing a 3 nm electron-blocking polymer layer. In addition, we reveal a giant voltage-dependent redshift of up to 62 meV due to the quantum-confined Stark effect and determine the exciton polarizability of the CdSe QD monolayer to be 4 × 10-5 meV/(kV/cm)2. These developments provide a foundation for accessing scalable quantum light sources and high-speed, tunable optoelectronic systems operating under ambient conditions.

Colloidal quasicrystals engineered with DNA.

In principle, designing and synthesizing almost any class of colloidal crystal is possible. Nonetheless, the deliberate and rational formation of colloidal quasicrystals has been difficult to achieve. Here we describe the assembly of colloidal quasicrystals by exploiting the geometry of nanoscale decahedra and the programmable bonding characteristics of DNA immobilized on their facets. This process is enthalpy-driven, works over a range of particle sizes and DNA lengths, and is made possible by the energetic preference of the system to maximize DNA duplex formation and favour facet alignment, generating local five- and six-coordinated motifs. This class of axial structures is defined by a square-triangle tiling with rhombus defects and successive on-average quasiperiodic layers exhibiting stacking disorder which provides the entropy necessary for thermodynamic stability. Taken together, these results establish an engineering milestone in the deliberate design of programmable matter.

SERS analysis of cancer cell-secreted purines reveals a unique paracrine crosstalk in MTAP-deficient tumors.

The tumor microenvironment (TME) is a dynamic pseudoorgan that shapes the development and progression of cancers. It is a complex ecosystem shaped by interactions between tumor and stromal cells. Although the traditional focus has been on the paracrine communication mediated by protein messengers, recent attention has turned to the metabolic secretome in tumors. Metabolic enzymes, together with exchanged substrates and products, have emerged as potential biomarkers and therapeutic targets. However, traditional techniques for profiling secreted metabolites in complex cellular contexts are limited. Surface-enhanced Raman scattering (SERS) has emerged as a promising alternative due to its nontargeted nature and simplicity of operation. Although SERS has demonstrated its potential for detecting metabolites in biological settings, its application in deciphering metabolic interactions within multicellular systems like the TME remains underexplored. In this study, we introduce a SERS-based strategy to investigate the secreted purine metabolites of tumor cells lacking methylthioadenosine phosphorylase (MTAP), a common genetic event associated with poor prognosis in various cancers. Our SERS analysis reveals that MTAP-deficient cancer cells selectively produce methylthioadenosine (MTA), which is taken up and metabolized by fibroblasts. Fibroblasts exposed to MTA exhibit: i) molecular reprogramming compatible with cancer aggressiveness, ii) a significant production of purine derivatives that could be readily recycled by cancer cells, and iii) the capacity to secrete purine derivatives that induce macrophage polarization. Our study supports the potential of SERS for cancer metabolism research and reveals an unprecedented paracrine crosstalk that explains TME reprogramming in MTAP-deleted cancers.

3D bioprinted breast tumor-stroma models for pre-clinical drug testing.

The use of three-dimensional (3D) bioprinting has been proposed for the reproducible production of 3D disease models that can be used for high-throughput drug testing and personalized medicine. However, most such models insufficiently reproduce the features and environment of real tumors. We report the development of bioprinted in vitro 3D tumor models for breast cancer, which physically and biochemically mimic important aspects of the native tumor microenvironment, designed to study therapeutic efficacy. By combining a mix of breast decellularized extracellular matrix and methacrylated hyaluronic acid with tumor-derived cells and non-cancerous stromal cells of biological relevance to breast cancer, we show that biological signaling pathways involved in tumor progression can be replicated in a carefully designed tumor-stroma environment. Finally, we demonstrate proof-of-concept application of these models as a reproducible platform for investigating therapeutic responses to commonly used chemotherapeutic agents.

Plexcitonic Nanorattles as Highly Efficient SERS-Encoded Tags.

Plexcitonic nanoparticles exhibit strong light-matter interactions, mediated by localized surface plasmon resonances, and thereby promise potential applications in fields such as photonics, solar cells, and sensing, among others. Herein, these light-matter interactions are investigated by UV-visible and surface-enhanced Raman scattering (SERS) spectroscopies, supported by finite-difference time-domain (FDTD) calculations. Our results reveal the importance of combining plasmonic nanomaterials and J-aggregates with near-zero-refractive index. As plexcitonic nanostructures nanorattles are employed, based on J-aggregates of the cyanine dye 5,5,6,6-tetrachloro-1,1-diethyl-3,3-bis(4-sulfobutyl)benzimidazolocarbocyanine (TDBC) and plasmonic silver-coated gold nanorods, confined within mesoporous silica shells, which facilitate the adsorption of the J-aggregates onto the metallic nanorod surface, while providing high colloidal stability. Electromagnetic simulations show that the electromagnetic field is strongly confined inside the J-aggregate layer, at wavelengths near the upper plexcitonic mode, but it is damped toward the J-aggregate/water interface at the lower plexcitonic mode. This behavior is ascribed to the sharp variation of dielectric properties of the J-aggregate shell close to the plasmon resonance, which leads to a high opposite refractive index contrast between water and the TDBC shell, at the upper and the lower plexcitonic modes. This behavior is responsible for the high SERS efficiency of the plexcitonic nanorattles under both 633 nm and 532 nm laser illumination. SERS analysis showed a detection sensitivity down to the single-nanoparticle level and, therefore, an exceptionally high average SERS intensity per particle. These findings may open new opportunities for ultrasensitive biosensing and bioimaging, as superbright and highly stable optical labels based on the strong coupling effect.

Tuning the Growth of Chiral Gold Nanoparticles Through Rational Design of a Chiral Molecular Inducer.

The bottom-up production of chiral gold nanomaterials holds great potential for the advancement of biosensing and nano-optics, among other applications. Reproducible preparations of colloidal nanomaterials with chiral morphology have been reported, using cosurfactants or chiral inducers such as thiolated amino acids. However, the underlying growth mechanisms for these nanomaterials remain insufficiently understood. We introduce herein a purposely devised chiral inducer, a cysteine modified with a hydrophobic chain, as a versatile chiral inducer. The amphiphilic and chiral features of this molecule provide control over the chiral morphology and the chiroptical signature of the obtained nanoparticles by simply varying the concentration of chiral inducer. These results are supported by circular dichroism and electromagnetic modeling as well as electron tomography to analyze structural evolution at the facet scale. Our observations suggest complex roles for the factors involved in chiral synthesis: the chemical nature of the chiral inducers and the influence of cosurfactants.

Photoluminescence upconversion in monolayer WSe2 activated by plasmonic cavities through resonant excitation of dark excitons.

Anti-Stokes photoluminescence (PL) is light emission at a higher photon energy than the excitation, with applications in optical cooling, bioimaging, lasing, and quantum optics. Here, we show how plasmonic nano-cavities activate anti-Stokes PL in WSe2 monolayers through resonant excitation of a dark exciton at room temperature. The optical near-fields of the plasmonic cavities excite the out-of-plane transition dipole of the dark exciton, leading to light emission from the bright exciton at higher energy. Through statistical measurements on hundreds of plasmonic cavities, we show that coupling to the dark exciton leads to a near hundred-fold enhancement of the upconverted PL intensity. This is further corroborated by experiments in which the laser excitation wavelength is tuned across the dark exciton. We show that a precise nanoparticle geometry is key for a consistent enhancement, with decahedral nanoparticle shapes providing an efficient PL upconversion. Finally, we demonstrate a selective and reversible switching of the upconverted PL via electrochemical gating. Our work introduces the dark exciton as an excitation channel for anti-Stokes PL in WSe2 and paves the way for large-area substrates providing nanoscale optical cooling, anti-Stokes lasing, and radiative engineering of excitons.