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Electrostatic interactions are a key driving force that mediates colloidal assembly. The Schulze-Hardy rule states that nanoparticles have a higher tendency to coagulate in the presence of counterions with high charge valence. However, it is unclear how the Schulze-Hardy rule works when the simple electrolytes are replaced with more sophisticated charge carriers. Here, we designed cationic peptides of varying valencies and demonstrate that their charge screening behaviors on anionic gold nanoparticles (AuNPs) follow the six-power relationship in the Schulze-Hardy rule. This finding further inspires a simple yet effective strategy for measuring SARS-CoV-2 main protease (Mpro) via naked eyes. This work provides a unique avenue for fundamental NP disassembly based on the Schulze-Hardy rule and can help design versatile substrates for colorimetric sensing of other proteases.

Plasmonic nanoparticles produce a localized surface plasmon resonance (LSPR) under optical excitation. The LSPR of nanoparticles can shift in response to changes in the local dielectric environment and produce a color change. This color change can be observed by the naked eye due to the exceptionally large extinction coefficients (10

Existing tools to detect and visualize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suffer from low selectivity, poor cell permeability, and high cytotoxicity. Here we report a novel self-immolative fluorescent probe (MP590) for the highly selective and sensitive detection of the SARS-CoV-2 main protease (Mpro). This fluorescent probe was prepared by connecting a Mpro-cleavable peptide (N-acetyl-Abu-Tle-Leu-Gln) with a fluorophore (i.e., resorufin) via a self-immolative aromatic linker. Fluorescent titration results show that MP590 can detect Mpro with a limit of detection (LoD) of 35 nM and is selective over interferents such as hemoglobin, bovine serum albumin (BSA), thrombin, amylase, SARS-CoV-2 papain-like protease (PLpro), and trypsin. The cell imaging data indicate that this probe can report Mpro in HEK 293T cells transfected with a Mpro expression plasmid as well as in TMPRSS2-VeroE6 cells infected with SARS-CoV-2. Our results suggest that MP590 can both measure and monitor Mpro activity and quantitatively evaluate Mpro inhibition in infected cells, making it an important tool for diagnostic and therapeutic research on SARS-CoV-2.

Synchronization is important for photoacoustic (PA) tomography, but some fixed delays between the data acquisition (DAQ) and the light pulse are a common problem degrading imaging quality. Here, we present a simple yet versatile method named "Scissors" to help synchronize ultrasound open platforms (UOPs) for PA imaging. Scissors is a programed function that can cut or add a fixed delay to radio frequency (RF) data and, thus, synchronize it before reconstruction. Scissors applies the programmable metric of UOPs and has several advantages. It is compatible with many setups regardless of the synchronization methods, light sources, transducers, and delays. The synchronization is adjustable in steps reciprocal to the UOPs' sampling rate (20-ns step with a 50-MHz sampling rate). Scissors works in real-time PA imaging, and no extra hardware is needed. We programed Scissors in Vantage UOP (Verasonics, Inc., Kirkland, WA, USA) and then imaged two 30- [Formula: see text] nichrome wires with a 20.2-MHz central frequency transducer. The PA image was severely distorted by an 828-ns delay; over 90% delay was caused by our Q -switch laser. The axial and lateral resolutions are 112 and [Formula: see text], respectively, after using Scissors. We imaged a human finger in vivo, and the imaging quality is tremendously improved after solving the 828-ns delay by using Scissors.

We report the peptide-programmed fractal assembly of silver nanoparticles (AgNPs) in a diffusion-limited aggregation (DLA) mode, and this change in morphology generates a significant color change. We show that peptides with specific repetitions of defined amino acids (i.e., arginine, histidine, or phenylalanine) can induce assembly and coalescence of the AgNPs (20 nm) into a hyperbranched structure (AgFSs) (~2 μm). The dynamic process of this assembly was systematically investigated, and the extinction of the nanostructures can be modulated from 400 to 600 nm by varying the peptide sequences and molar ratio. According to this rationale, two strategies of SARS-CoV-2 detection were investigated. The activity of the main protease (Mpro) involved in SARS-CoV-2 was validated with a peptide substrate that can bridge the AgNPs after the proteolytic cleavage. A subnanomolar limit of detection (0.5 nM) and the capacity to distinguish by the naked eye in a wide concentration range (1.25–30 nM) were achieved. Next, a multichannel sensor-array based on multiplex peptides that can visually distinguish SARS-CoV-2 proteases from influenza proteases in doped human samples was investigated.

Plant viral nanoparticles (plant VNPs) are promising biogenetic nanosystems for the delivery of therapeutic, immunotherapeutic, and diagnostic agents. The production of plant VNPs is simple and highly scalable through molecular farming in plants. Some of the important advances in VNP nanotechnology include genetic modification, disassembly/reassembly, and bioconjugation. Although effective, these methods often involve complex and timeconsuming multi-step protocols. Here, we report a simple and versatile supramolecular coating strategy for designing functional plant VNPs via metal–phenolic networks (MPNs). Specifically, this method gives plant viruses [e.g., tobacco mosaic virus (TMV), cowpea mosaic virus, and potato virus X] additional functionalities including photothermal transduction, photoacoustic imaging, and fluorescent labeling via different components in MPN coating [i.e., complexes of tannic acid (TA), metal ions (e.g., Fe(3+), Zr(4+), or Gd(3+)), or fluorescent dyes (e.g., rhodamine 6G and thiazole orange)]. For example, using TMV as a viral substrate by choosing Zr(4+)–TA and rhodamine 6G, fluorescence is observed peaking at 555 nm; by choosing Fe(3+)–TA coating, the photothermal conversion efficiency was increased from 0.8 to 33.2%, and the photoacoustic performance was significantly improved with a limit of detection of 17.7 μg mL(−1). We further confirmed that TMV@Fe(3+)–TA nanohybrids show good cytocompatibility and excellent cell-killing performance in photothermal therapy with 808 nm irradiation. These findings not only prove the practical benefits of this supramolecular coating for designing multifunctional and biocompatible plant VNPs but also bode well for using such materials in a variety of plant virus-based theranostic applications.

Chronic wounds are a major health problem that cause the medical infrastructure billions of dollars every year. Chronic wounds are often difficult to heal and cause significant discomfort. Although wound specialists have numerous therapeutic modalities at their disposal, tools that could 3D-map wound bed physiology and guide therapy do not exist. Visual cues are the current standard but are limited to surface assessment; clinicians rely on experience to predict response to therapy. Photoacoustic (PA) ultrasound (US) is a non-invasive, hybrid imaging modality that can solve these major limitations. PA relies on the contrast generated by hemoglobin in blood which allows it to map local angiogenesis, tissue perfusion and oxygen saturation—all critical parameters for wound healing. This work evaluates the use of PA-US to monitor angiogenesis and stratify patients responding vs. not-responding to therapy. We imaged 19 patients with 22 wounds once a week for at least three weeks. Our findings suggest that PA imaging directly visualizes angiogenesis. Patients responding to therapy showed clear signs of angiogenesis and an increased rate of PA increase (p = 0.002). These responders had a significant and negative correlation between PA intensity and wound size. Hypertension was correlated to impaired angiogenesis in non-responsive patients. The rate of PA increase and hence the rate of angiogenesis was able to predict healing times within 30 days from the start of monitoring (power = 88%, alpha = 0.05) This early response detection system could help inform management and treatment strategies while improving outcomes and reducing costs.

Gold nanorods (GNRs) have attracted great interest for photo-mediated biomedicines due to their tunable and high optical absorption, high photothermal conversion efficiency and facile surface modifiability. GNRs that have efficient absorption in second near-infrared (NIR-II) window hold further promise in bio-applications due to low background signal from tissue and deep tissue penetration. However, bare GNRs readily undergo shape deformation (termed as 'melting effect') during the laser illumination losing their unique localized surface plasmon resonance (LSPR) properties, which subsequently leads to PA signal attenuation and decreased photothermal efficiency. Polydopamine (PDA) is a robust synthetic melanin that has broad absorption and high photothermal conversion. Herein, we coated GNRs with PDA to prepare photothermally robust GNR@PDA hybrids for enhanced photo-mediated theranostic agents. Ultrasmall GNRs (SGNRs) and conventional large GNRs (LGNRs) that possess similar LSPR characteristics as well as GNR@PDA hybrids were compared side-by-side in terms of the size-dependent photoacoustic (PA) imaging, photothermal therapy (PTT), and structural stability. In vitro experiments further demonstrated that SGNR@PDA showed 95% ablation of SKOV3 ovarian cancer cells, which is significantly higher than that of LGNRs (66%) and SGNRs (74%). Collectively, our PDA coating strategy represents a rational design for enhanced PA imaging and efficient PTT via a nanoparticle, i.e., nanotheranostics.

Photoacoustic (PA) imaging has proved versatile for many biomedical applications from drug delivery tracking to disease diagnostics and postoperative surveillance. It recently emerged as a tool for accurate and real-time heparin monitoring to avoid bleeding complications associated with anticoagulant therapy. However, molecular-dye-based application is limited by high concentration requirements, photostability, and a strong background hemoglobin signal. We developed polydopamine nanocapsules (PNCs)ivia/isupramolecular templates and loaded them with molecular dyes for enhanced PA-mediated heparin detection. Depending on surface charge, the dye-loaded PNCs undergo disassembly or aggregation upon heparin recognition: both experiments and simulation have revealed that the increased PA signal mainly results from dye-loaded PNC-heparin aggregation. Importantly, Nile blue (NB)-loaded PNCs generated a 10-fold higher PA signal than free NB dye, and such PNC enabled the direct detection of heparin in a clinically relevant therapeutic window (0-4 U/mL) in whole human blood (iR/isup2/sup= 0.91). Furthermore, the PA signal of PNC@NB obtained from 17 patients linearly correlated with ACT values (iR/isup2/sup= 0.73) and cumulative heparin (iR/isup2/sup= 0.83). This PNC-based strategy for functional nanocapsules offers a versatile engineering platform for robust biomedical contrast agents and nanocarriers.

Aromatic interactions are commonly involved in the assembly of naturally occurring building blocks, and these interactions can be replicated in an artificial setting to produce functional materials. Here we describe a colorimetric biosensor using co-assembly experiments with plasmonic gold and surfactant-like peptides (SLPs) spanning a wide range of aromatic residues, polar stretches, and interfacial affinities. The SLPs programmed in DDD−(ZZ)x−FFPC self-assemble into higher-order structures in response to a protease and subsequently modulate the colloidal dispersity of gold leading to a colorimetric readout. Resultsshow the strong aggregation propensity of the FFPC tail without polar DDD head. The SLPs were specific to the target protease, i.e., Mpro, a biomarker for SARS-CoV-2. This system is a simple and visual tool that senses Mproin phosphate buffer, exhaled breath condensate, and saliva with detection limits of 15.7, 20.8, and 26.1 nM, respectively. These results may have value in designing other protease testing methods. Submitted/Accepted version The authors thank internal funding from the UC Office of the President (R00RG2515) and the National Institutes of Health (R01 DE031114; R21 AG065776-S1; R21 AI157957) for financial support. This work was also supported by National Science Foundation (DMR-2011924) via equipment in the UC San Diego Materials Research Science and Engineering Center (UCSD MRSEC). M.N.C. was supported by NIT under T32 CA15391.M.R. acknowledges the Wallonie-Bruxelles International (WBI) of the Fédération Wallonie-Bruxelles for financial support. The electron microscopy work was performed in part at the San Diego Nanotechnology Infrastructure (SDNI) of University of California San Diego, a member of the National Nanotechnology Coordinated Infrastructure (NNCI), which is supported by the National Science Foundation (Grant ECCS-1542148). The MANTA analysis work was supported by the National Institutes of Health (S10 OD023555).

Polymer nanocapsules have demonstrated significant value in materials science and biomedical technology, but require complicated and time-consuming synthetic steps. We report here the facile synthesis of monodisperse polymer nanocapsules via a redox-mediated kinetic strategy from two simple molecules: dopamine and benzene-1,4-dithiol (BDT). Specifically, BDT forms core templates and modulates the oxidation kinetics of dopamine into polydopamine (PDA) shells. These uniform nanoparticles can be tuned between ≈70 and 200 nm because the core diameter directly depends on BDT while the shell thickness depends on dopamine. The supramolecular core can then rapidly disassemble in organic solvents to produce PDA nanocapsules. Such nanocapsules exhibit enhanced physicochemical performance (e.g., loading capacity, photothermal transduction, and anti-oxidation) versus their solid counterparts. Particularly, this method enables a straightforward encapsulation of functional nanoparticles providing opportunities for designing complex nanostructures such as yolk-shell nanoparticles.

Gold nanorods possess optical properties that are tunable and highly sensitive to variations in their aspect ratio (length/width). Therefore, the development of a sensing platform where the gold nanorod morphology (i.e., aspect ratio) is modulated in response to an analyte holds promise in achieving ultralow detection limits. Here, we use a dithiol peptide as an enzyme substrate during nanorod growth. The sensing mechanism is enabled by the substrate design, where the dithiol peptide contains an enzyme cleavage site in-between cysteine amino acids. When cleaved, the peptide dramatically impacts gold nanorod growth and the resulting optical properties. We demonstrate that the optical response can be correlated with enzyme concentration and achieve a 45 pM limit of detection. Furthermore, we extend this sensing platform to colorimetrically detect tumor-associated inhibitors in a biologically relevant medium. Overall, these results present a subnanomolar method to detect proteases that are critical biomarkers found in cancers, infectious diseases, and inflammatory disorders.

We report the reversible aggregation of gold nanoparticles (AuNPs) assemblies via a di-arginine peptide additive and thiolated PEGs (HS-PEGs). The AuNPs were first aggregated by attractive forces between the citrate-capped surface and the arginine side chains. We found that the HS-PEG thiol group has a higher affinity for the AuNP surface, thus leading to redispersion and colloidal stability. In turn, there was a robust and obvious color change due to on/off plasmonic coupling. The assemblies' dissociation was directly related to the HS-PEG structural properties such as their size or charge. As an example, HS-PEGs with a molecular weight below 1 kDa could dissociate 100% of the assemblies and restore the exact optical properties of the initial AuNP suspension (prior to the assembly). Surprisingly, the dissociation capacity of HS-PEGs was not affected by the composition of the operating medium and could be performed in complex matrices such as plasma, saliva, bile, urine, cell lysates, or even seawater. The high affinity of thiols for the gold surface encompasses by far the one of endogenous molecules and is thus favored. Moreover, starting with AuNPs already aggregated ensured the absence of a background signal as the dissociation of the assemblies was far from spontaneous. Remarkably, it was possible to dry the AuNP assemblies and solubilize them back with HS-PEGs, improving the colorimetric signal generation. We used this system for protease sensing in biological fluids. Trypsin was chosen as the model enzyme, and highly positively charged peptides were conjugated to HS-PEG molecules as cleavage substrates. The increase of positive charge of the HS-PEG-peptide conjugate quenched the dissociation capacity of the HS-PEG molecules, which could only be restored by the proteolytic cleavage. Picomolar limit of detection was obtained as well as the detection in saliva or urine.

Plasmonic coupling

Diseases of the microcirculatory system are well-known risk factors for chronic wound healing. Hyperbaric oxygen therapy (HBO2) is a common therapeutic modality that drives oxygen into hypoxic tissue to promote healing. Ischemia/hypoxia are common confounding variables associated with failure of wound progress and/or relapse, and hence it is important to develop tools that map and measure perfusion and oxygen saturation in the wound bed. Photoacoustic (PA) imaging is an ideal tool to address these concerns. Ten patients undergoing HBO2 underwent PA oximetry of the left radial artery and forearm pre- and post-HBO2; this cohort validated the use of PA imaging in HBO2. There was a significant increase in radial artery oxygenation after HBO2 (p=0.002) in the validation cohort. PA significantly underestimated arterial oxygenation compared to a pulse oximeter. We also include a case study: a non-diabetic male in his 50s (HB 010) presenting with bilateral ischemic and gangrenous wounds. HB 010 underwent additional scanning of the wound sites both pre- and post-HBO2. HB 010 showed higher perfusion and oxygen saturation on the right foot than the left after HBO2 which correlated with independent surgical observations. Imaging assisted with limb salvage treatment options by limiting the initial amputation site to only the toes. Hence, this work shows that PA imaging can measure changes in arterial oxygen saturation due to HBO2; it can also produce 3D maps of tissue oxygenation and evaluate response to therapy during HBO2.Key PointsPhotoacoustic oximetry can measure and map changes in arterial oxygenation due to hyperbaric oxygen therapy. Photoacoustic imaging shows changes in perfusion in a patient presenting with bilateral ischemic and gangrenous wounds and thus informing limb salvage treatment.

We report the reversible aggregation of gold nanoparticle (AuNPs) assemblies via a diarginine peptide additive and thiolated PEGs (HS-PEGs). The AuNPs were first aggregated by attractive forces between the citrate-capped surface and the arginine side chains. We found that HS-PEG thiol group has higher affinity for the AuNPs surface, thus leading to redispersion and colloidal stability. In turn, there was a robust and obvious color change due to on/off plasmonic coupling. The assemblies’ dissociation was directly related to the HS-PEG structural properties such as their size or charge. As an example, HS-PEGs with a molecular weight below 1 kDa could dissociate 100% of the assemblies and restore the exact optical properties of the initial AuNPs suspension (prior to the assembly). Surprisingly, the dissociation capacity of HS-PEGs was not affected by the composition of the operating medium and could be performed in complex matrices such as plasma, saliva, bile, urine, cell lysates or even sea water. The high affinity of thiols for the gold surface encompasses by far the one of endogenous molecules and is thus favorized. Moreover, starting with AuNPs already aggregated ensured the absence of background signal as the dissociation of the assemblies was far from spontaneous. Remarkably, it was possible to dry the AuNPs assemblies and to solubilize them back with HS-PEGs, improving the colorimetric signal generation. We used this system for protease sensing in biological fluid. Trypsin was chosen as model enzyme and highly positively charged peptides were conjugated to HS-PEG molecules as cleavage substrate. The increase of positive charge of the HS-PEG-peptide conjugate quenched the dissociation capacity of the HS-PEG molecules which could only be restored by the proteolytic cleavage. Picomolar limit of detection was obtained as well as the detection in saliva or urine.TOC

Nucleic acids are well-established biomarkers of cancer with immense value in diagnostics and basic research. However, strategies to monitor these species in tissue can be challenging due to the need for amplification of imaging signal from low analyte concentrations with high specificity. Photoacoustic (PA) imaging is gaining traction for molecular imaging of proteins, small biomolecules, and nucleic acids by coupling pulsed near-infrared (NIR) excitation with broadband acoustic detection. This work introduces a PA nucleic acid contrast agent that harnesses NIR fluorophore and quencher-tagged hybridization chain reaction (HCR) for signal amplification. This HCR probe was designed to enable contact quenching between NIR dye-quencher pairs by coercing their direct alignment when miR-21, a microRNA cancer biomarker, is detected. The probe demonstrated a ratiometric PA limit of detection of 148 pM miR-21, sequence specificity against one- and two-base mutations, and selectivity over other microRNAs. It was further tested in live human ovarian cancer (SKOV3) and noncancerous (HEK 293T) cells to exemplify in situ PA activation based on differences in endogenous miR-21 regulation (p = 0.0002). The probe was lastly tested in tissue mimicking phantoms to exemplify sustained contrast in centimeter-range depths and 85.3% photostability after 15 min of laser irradiation. The probe's miR-21-specific activation and its ability to maintain contrast in biologically relevant absorbing and scattering media support its consideration for live-cell PA microscopy and potential cancer diagnostics. Results from this probe also underscore the combined detection power between ratiometric PA signaling and strand amplification for more sensitive DNA-based PA sensors.

Interfacial modular assembly has emerged as an adaptable strategy for engineering the surface properties of substrates in biomedicine, photonics, and catalysis. Herein, we report a versatile and robust coating (pBDT-TA), self-assembled from tannic acid (TA) and a self-polymerizing aromatic dithiol (i.e., benzene-1,4-dithiol, BDT), that can be engineered on diverse substrates with a precisely tuned thickness (5-40 nm) by varying the concentration of BDT used. The pBDT-TA coating is stabilized by covalent (disulfide) bonds and supramolecular (π-π) interactions, endowing the coating with high stability in various harsh aqueous environments across ionic strength, pH, temperature (e.g., 100 mM NaCl, HCl (pH 1) or NaOH (pH 13), and water at 100 °C), as well as surfactant solution (e.g., 100 mM Triton X-100) and biological buffer (e.g., Dulbecco's phosphate-buffered saline), as validated by experiments and simulations. Moreover, the reported pBDT-TA coating enables secondary reactions on the coating for engineering hybrid adlayers (e.g., ZIF-8 shells) via phenolic-mediated adhesion, and the facile integration of aromatic fluorescent dyes (e.g., rhodamine B) via π interactions without requiring elaborate synthetic processes.

Organic nanomaterials increasingly generate interest from diverse fields spanning fundamental and clinical research, biotechnology, and nanomedicine. Organic nanomaterials are exceptionally versatile, with applications in several domains: molecular imaging, pharmaceutical formulations, and imageguided therapies. Unlike inorganic nanomaterials, these materials offer distinct advantages, such as facile tunability in composition or surface functionalization, excellent biocompatibility, controlled release, and so on. Here, motivated by the considerable development and application of organic nanomaterials in life science, we summarize recent progress in using organic nanomaterials for bioimaging, drug delivery, and therapy.

Facemasks in congregate settings prevent the transmission of SARS-CoV-2 and help control the ongoing COVID-19 global pandemic because face coverings can arrest transmission of respiratory droplets. While many groups have studied face coverings as personal protective equipment, these respiratory droplets can also serve as a diagnostic fluid to report on health state; surprisingly, studies of face coverings from this perspective are quite limited. Here, we determined the concentration and distribution of aerosolized saliva (via α-amylase levels) captured on various face coverings. Our results showed that α-amylase accumulated on face coverings in a time-dependent way albeit at different levels, e.g., neck gaiters and surgical masks captured about 3-fold more α-amylase than cloth masks and N95 respirators. In addition, the saliva aerosols were primarily detected on the inner layer of multilayered face coverings. We also found that the distribution of salivary droplets on the mask correlated with the morphologies of face coverings as well as their coherence to the face curvature. These findings motivated us to extend this work and build multifunctional sensing strips capable of detecting biomarkers in situ to create “smart” masks. The work highlights that face coverings are promising platforms for biofluid collection and colorimetric biosensing, which bode well for developing surveillance tools for airborne diseases.

Inorganic nanomaterials hold immense potential in theranostics, but their translation is limited by the toxicity resulting from non-degradability. Bulk phosphate-based glasses offer great biodegradability, biocompatibility, and ease in incorporating imaging dyes and drugs. However, the facile and mild solution-based synthesis of micro-/nanoparticles of this material is yet to be explored. Inspired by the biosilicification process in the diatom, we created polyethylenimine (PEI)/phosphate aggregates via the hydrogen bonding between amine (PEI) and hydroxyl (phosphate) groups, which was proved by dynamic light scattering and 1H solution nuclear magnetic resonance. The sol–gel reaction between the calcium precursor and PEI/phosphate aggregates yielded degradable PEI/calcium phosphate (PEI/CP) micro-/nano-composites with versatile sizes (396 ± 128 nm to 63 ± 8 μm) and morphologies (hexagonal micro-disc, micro-flower, micro-leaf, nano-butterfly, and nano-ribbon). The PEI/CP composition and chemical structure were examined. PEI/CP has negligible cell cytotoxicity and degrades within 24 h. In vitro studies showed the promise for PEI/CP in transient ultrasound and photoluminescence imaging.\ud \ud

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious threat to human health and lacks an effective treatment. There is an urgent need for both real-time tracking and precise treatment of the SARS-CoV-2-infected cells to mitigate and ultimately prevent viral transmission. However, selective triggering and tracking of the therapeutic process in the infected cells remains challenging. Here, we report a main protease (M

Porphyromonas gingivalis is a keystone pathogen in periodontal disease. We herein report a dual-modal fluorescent and photoacoustic imaging probe for the detection of gingipain proteases secreted by P. gingivalis. Upon proteolytic cleavage by Arg-specific gingipain (RgpB), five-fold photoacoustic enhancement and100-fold fluorescence activation was measured with detection limits of 1.1 nM RgpB and 5.0E4 CFU mL

Phosphate-based glasses are well-studied biodegradable materials in the bulk. However, less is known about the synthesis and properties of phosphate glass when prepared as microparticles or nanopar...

The recent development of gold nanoparticles as diagnostic tools is burgeoning, especially in the cancer community with a focus on theranostic applications to both cancer diagnosis and treatment. Gold nanoparticles have also demonstrated great potential for use in diagnostic and therapeutic approaches in ophthalmology. Although many ophthalmic imaging modalities are available, there is still a considerable unmet need, in particular for ophthalmic molecular imaging for the early detection of eye disease before morphological changes are more grossly visible. An understanding of how gold nanoparticles are leveraged in other fields could inform new ways they could be utilized in ophthalmology. In this paper, we review current ophthalmic imaging techniques and then identify optical coherence tomography (OCT) and photoacoustic imaging (PAI) as the most promising technologies amenable to the use of gold nanoparticles for molecular imaging. Within this context, the development of gold nanoparticles as OCT and PAI contrast agents are reviewed, with the most recent developments described in detail. Gold nanoparticles are promising OCT and PAI contrast agents for eye imaging because of their high light scattering/absorption from SPR