The Promise of Nanoplasmonic Sensing for Extracellular Vesicles and Bacterial Membrane Vesicles
Extracellular vesicles (EVs) and bacterial membrane vesicles (MVs) have emerged as promising biomarkers for early disease diagnosis, prognosis, and environmental monitoring. However, the detection and analysis of these tiny vesicles present significant challenges that have slowed their clinical translation. Nanoplasmonic sensing techniques offer a remarkable solution, providing extreme sensitivity, selectivity, and versatility in identifying EVs and bacterial MVs.
In this comprehensive review, we explore the fundamentals of nanoplasmonic sensing and delve into the latest advancements in optical sensors tailored for EV and bacterial MV detection. From localized surface plasmon resonance (LSPR) to surface plasmon polaritons (SPP) and surface-enhanced Raman spectroscopy (SERS), we examine how these cutting-edge techniques are revolutionizing the field of molecular diagnostics and environmental monitoring.
Localized Surface Plasmon Resonance for EV and Bacterial MV Sensing
Nanoplasmonic antennas, particularly gold nanoparticles (GNPs), exhibit exceptional light-matter interaction compared to dielectric materials of similar size. The oscillation of electron clouds on the surface of metallic nanoparticles, known as LSPR, can be harnessed to detect the presence and characteristics of EVs and bacterial MVs.
One innovative approach involves the in-situ growth of a gold nanoshell around an EV template, causing a substantial shift in the LSPR absorbance wavelength that can be easily detected, even with a smartphone camera. This technique has demonstrated a detection limit of 1500 EVs, offering 1000 times better sensitivity than traditional ELISA methods.
GNP-labeled lateral flow immunoassays (LFIA) have also emerged as a promising low-cost, point-of-care solution for EV sensing. The GNP labels enable colorimetric detection of EVs captured by specific antibodies, achieving a detection limit of 8.5 × 10^5 EVs per μL. The small size of GNPs allows for multiplexed detection on a single LFIA strip, opening up new possibilities for simultaneous analysis of various EV biomarkers.
Beyond simple LSPR-based sensing, plasmonic resonance energy transfer (PRET) has enabled the non-destructive, label-free monitoring of critical molecules like cytochrome C and cytochrome P450 within living cells. This approach can be extended to detect enzymes released by bacterial MVs, providing valuable insights into microbial activity and environmental conditions.
Surface Plasmon Polaritons for Advanced EV Detection
While LSPR-based sensors excel in their simplicity and versatility, surface plasmon polaritons (SPP) offer enhanced sensitivity due to the propagation of electron oscillations along a plasmonic thin film surface. The evanescent field generated by the SPP can effectively probe and detect the binding of EVs to the sensor surface.
Nanostructured plasmonic thin films, such as those with periodic nanoholes, have demonstrated remarkable performance in EV detection. The extraordinary optical transmission (EOT) effect in these substrates enables the sensitive monitoring of EV binding, achieving detection limits up to four orders of magnitude better than traditional western blot techniques.
Combining localized and propagating surface plasmons has also led to innovative hybrid platforms, such as photonic crystal-plasmonic structures, which leverage the benefits of both to achieve highly sensitive EV detection. These advanced substrates can deliver spectral shifts of up to 80 nm upon EV binding, showcasing their potential for precise, quantitative analysis.
Surface-Enhanced Raman Spectroscopy for Molecular Fingerprinting of EVs and Bacterial MVs
While LSPR and SPP sensors excel at detecting the presence and concentration of EVs and bacterial MVs, surface-enhanced Raman spectroscopy (SERS) offers a unique capability: the ability to obtain molecular fingerprints of these vesicles. By leveraging the intense electromagnetic field enhancement provided by plasmonic nanostructures, SERS can reveal the distinct Raman signatures of proteins, lipids, and other biomolecules within EVs and bacterial MVs.
SERS has demonstrated the potential to distinguish between normal and cancerous EVs based on their unique Raman profiles, achieving classification accuracies of up to 97.3% in lung cancer detection. The heterogeneous nature of EVs and bacterial MVs can be harnessed to provide valuable information about their cellular origin, cargo composition, and potential disease associations.
Innovative SERS substrate designs, such as beehive-inspired inverse opal structures and vertically aligned gold nanorods, have further enhanced the detection capabilities of this technique. By effectively trapping and isolating EVs and bacterial MVs within their porous or nanogap architectures, these substrates enable efficient SERS signal acquisition and analysis.
Challenges and Future Directions
While nanoplasmonic sensing techniques have made remarkable progress in EV and bacterial MV detection, several challenges remain to be addressed for their widespread adoption in clinical and environmental applications.
Integrating sample preparation and sensor chips into a seamless “sample-to-answer” platform is a critical next step to facilitate point-of-care diagnostics and on-site environmental monitoring. Rapid EV isolation methods, such as the recently developed EXODUS technique, must be combined with compact, user-friendly sensor devices to enable truly transformative solutions.
Enhancing sensor throughput and multiplexing capabilities is another key priority, as it will enable the simultaneous detection of multiple biomarkers and accelerate clinical research and commercialization. Advancements in portable spectrometers and the integration of machine learning algorithms can greatly contribute to this goal.
Furthermore, improving the portability and miniaturization of SERS instrumentation is essential to realize the full potential of molecular fingerprinting for EVs and bacterial MVs. Leveraging emerging technologies, such as graphene plasmonics and metamaterial-based sensors, may unlock new opportunities in this direction.
As nanoplasmonic sensing continues to evolve, it holds immense promise in revolutionizing the fields of early disease diagnosis, prognosis, and environmental monitoring. By overcoming the current challenges, these advanced optical sensors are poised to become indispensable tools in the quest for personalized healthcare and sustainable ecosystem management.
