Cancer has become one of the most deadly diseases throughout the world, with nearly 2 million new cases and over half a million deaths in the U.S. in 2022 alone ^[1][2][1,2]. Of the more deadly cancers, glioblastoma (GBM), is an especially devastating cancer of the brain ^[3][4][3,4]. GBM patient survival rate is a rather dismal at 15 months, even after treatments such as surgery, chemotherapy, and X-ray radiotherapy (XRT) ^[3][4][3,4]. Despite enormous efforts, GBM is still a deadly disease with essentially 100% mortality, urging for new treatment methods. Cancer detection has traditionally relied on techniques that can penetrate thick tissue and produce images that delineate non-tumor tissue from normal tissue based on its structure and density. Modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) are particularly effective in delineating tumor masses from normal tissue, as cancer tissue often has an abnormal tissue density compared with its local environment ^[5][6][5,6]. However, these modalities are often limited as they require highly trained doctors and technicians who can interpret CT and MRI data to make a diagnosis. Additionally, these methods require further interrogations of suspected tumors via histopathology to ascertain the presence of cancerous growth [7].

To overcome these issues, optical modalities that probe the biomolecular composition of the tissue itself have been developed to non-invasively diagnose cancer. Methods such as absorption, fluorescence, and Raman spectroscopy are all modalities that can probe for the unique biochemical composition of cancer tissue, allowing for in vivo imaging that provides a high molecular specificity ^{[8][9][10][11][12][13][14]}[8,9,10,11,12,13,14]. The absorption and scattering optical properties are distinct in different tissues and serve as the contrasting property of modalities such as diffuse optical tomography (DOT) ^[9][15][9,15]. On the other hand, fluorescence arises from the sum of different metabolic fluorescence molecules, which can serve as an effective indicator for tumor tissues that have abnormal metabolic rates [10]. Raman spectroscopy is the most specific as the spectral fingerprint of a molecule will have unique Raman peaks at specific Raman shift values.

All of these methods can be utilized with minimal equipment and training, and thus could be useful for rapid diagnostic imaging. However, intrinsic signal differences between tumor and non-tumor tissue can be noisy. In the case of Raman spectroscopy, other sources of signals such as fluorescence may overwhelm the weak Raman scattering signal [16]. One way to overcome this limitation is to use a fluorescent or Raman dye targeted to the tumor ^[17][18][19][17,18,19]. This can be achieved with methods such as antibody targeting, but recently, nanoparticles have become an ideal choice as a delivery platform as they can take advantage of the enhanced permeation and retention (EPR) effect in which the leaky vasculature of tumor sites allows for nanoparticle accumulation to the local tumor site ^[17][20][17,20]. Additionally, the use of gold, which is a biocompatible material, allows for flexible chemical conjugation of drugs or dyes into these particles, allowing for multifunctional uses of detection and treatment ^[18][21][22][18,21,22]. Gold nanoparticles, such as gold nanoshells, have been used for photothermal ablation of prostate tumors in clinical trials with no significant toxicities [23]. In addition, a first-in-human clinical study of RNA interference-based spherical nucleic acids, which consist of gold nanoparticle cores, was conducted in patients with recurrent glioblastoma and it revealed no grade 4 or 5 treatment-related toxicities [24]. Finally, these metallic nanoparticles have a unique absorption signature that makes them ideal for targeted thermal therapy ^[20][25][26][20,25,26].

2. Plasmonic Nanoparticles for Tumor Imaging and Treatment

Plasmonic-active nanosystems such as metallic nanostructures and nanoparticles have recently seen a wide usage of applications ranging from diagnostics to therapy. Plasmonics is a field associated with the induced oscillation of conduction electrons found in metallic nanoscale structures using a source such as laser light. These electron oscillations, or surface plasmons, produce a secondary electromagnetic field that augments the incident electromagnetic field, resulting in a large electromagnetic field around the nanostructure. Numerous plasmonic-active nanoparticles of different geometric shapes and metallic compositions have been developed for tumor imaging. Gold nanospheres have also been used and have seen applications ranging from photothermal generation to drug delivery ^[27][28][29][27,28,29]. They have also been used as the core to larger nanoparticle constructs used in multimodal applications such as in ultrasound and photoacoustic imaging coupled with fluorescence ^[30][31][30,31]. Other particles such as the gold nanoshell are specifically tuned to near IR absorption to allow for reaching maximal in-depth tissue for cancer therapy ^{[23][27][32][33][34]}[23,27,32,33,34]. Among the nanoparticles with different morphologies and shapes, GNS is among the most effective nanoplatforms for its unique star-shaped geometry and optical tunability ^[35][36][37][35,36,37]. The plasmonic E-field enhancement is concentrated around the tips of each star, which act as a “lightning rod” that greatly exceeds the enhancement of smoother particles such as nanospheres ^[38][39][38,39]. This electromagnetic (EM) field greatly increases Raman scattering near the surface of the metal in what is known as surface-enhanced Raman scattering (SERS), allowing for chemical species adsorbed on or near the surface of the metal to have a very strong Raman signal. ReseaOurchers' laboratory has developed a variety of metallic nanoparticles for SERS applications in chemical analysis, sensing, and diagnostics ^{[40][41][42][43]}[40,41,42,43]. This EM field enhancement around the nanoparticle manifests in a highly absorbing nanoparticle that has a high photon-to-heat conversion [17]. As a demonstration of theranostics, reswearchers developed a specially designed multifunctional gold nanostar with multiple functionalities in detection (SERS, MRI, CT, and TPL) and photothermal treatment (PTT), allowing for pre-operative macroscopic imaging as well as photothermal therapy for post-operative treatment [18]. Furthermore, our group has specifically developed a surfactant-free fabrication of GNS unlike many other similar gold nanoparticle synthesis methods ^[37][39][37,39]. This allows for an even greater biocompatibility for in vivo applications. Additionally, the surface can easily be functionalized with a variety of other reporters for imaging modalities such as MRI [18].

3. Photothermal Therapy (PTT)

The GNS nanoparticles’ multiple sharp branches result in tip-enhanced plasmonics for imaging and PTT ^[44][45][46][45,53,54]. Upon irradiation with a laser light source, the surface electrons on the metal are thrown into oscillations and induce a strong EM force field. These oscillating plasmons can be roughly modeled after the Drude model of electric conduction at the nanometer scale. Previously, reseaourchers' group developed several models with finite element software (COMSOL Multiphysics) to determine the bulk absorption profile across different wavelengths ^[38][44][46][38,45,54]. This is particularly important as optical tuning of GNS is possible by controlling the amount of gold or silver added in the synthesis of the particles, and the peak absorption can be red or blue shifted depending on the final size of the particles ^[35][37][39][35,37,39]. For example, adding more silver chloride reactant in the synthesis notably red-shifts the peak absorption [39]. To this end, rwesearchers developed GNS targeted at the near-infrared (NIR) spectral range (700–1100 nm) within the so-called “tissue optical window”, which corresponds to the wavelength range of least absorption by the tissue ^[35][37][44][35,37,45]. The thermal treatment of tumors can be achieved conventionally using microwave or high-intensity focused ultrasound. However, such methods are not suitable for deep-seated tumors and off-target heating is often a problem. To circumvent this issue, rwesearchers utilize GNS to take advantage of the EPR effect and only allowed GNS to accumulate around the tumor tissue. As gold nanoparticles are relatively inert, off-target accumulation is not a concern and PTT will only occur in tissue directly irradiated by the laser. This NIR window is particularly important as targeting this range allows for maximal tissue penetration by the traveling photons and minimal absorption around the surrounding tissue. By using the accumulated GNS as the heat nanogenerators selectively absorbed inside tumors via the EPR effect, rather than heating the entire tissue itself, off-target heating can be greatly reduced.