Light develops physiological changes in cells and stimulates an endogenous biological chemical reaction either directly or indirectly [8,24]. The light-based biochemical activity can be extensively classified into those relying on the applications of photoconversion efficiency. In PDT, organic/inorganic nanoparticles can absorb light, this will then stimulate the chemical changes leading to the therapeutic outcome. While in PTT, the absorbed light by inorganic nanoparticles will stimulate the transformation of irradiating laser into localized thermal energy [8,19]. Other approaches utilize the capacity of GNPs to develop high energetic radiation (radiotherapy) to focus therapy on the cancer region. The potential merits of phototherapies are minimal cytotoxicity, invasive, and specific tumor ability [17]. Commonly, lasers are applied as radiation sources for photo-based cancer theranostics which can produce a monochromatic light that can be allowed via an optical fiber and attainted the target region directly [25]. The wavelength of the laser irradiation should depend on the capability to absorb the light by photosensitizers (PS), the location of the tumor, size, and various other factors to standardize the activation of the PS [27,28]. For effective clinical practice, phototherapies are strongly dependent on wavelength, exposure duration, penetration power, mode of delivery, and total dose of the light [29]. From 600 to 800 nm is the common wavelength range applied for phototherapies named a therapeutic window, within this wavelength, the energy of radiation can excite the PS permitting efficient tissue penetration but restricting the absorption of light by other cellular parts (cytochromes) [28]. PDT consists of three potential components as Oxygen, PS, and light source for cancer therapy [30]. One major advantage of PDT, it can proceed in the repetitive mode without generating immune/myelosuppressive effects and is also administered even after traditional therapies. The standard PS ligand should be a single pure molecule that permits quality assurance research with resonance stability. The PS can administer via topical or intravenous injections. However, the alteration in biodistribution over a long duration gets affected; the alternative path to regulate the impact of PDT is the duration of light exposure.

The laser absorption, the sensitizer, is transformed from a single state (short-lived) to a triplet state (long-lived). This triple state responds in two types such as (i) triple state reacts directly to the cell membrane and transfers the molecules into free radicals. When these free radicals react with oxygen molecules to form the oxygenated products (type I). (ii) Another way, the triple state can transfer its energy to the oxygen molecules and transform the singlet oxygen into a reactive oxygen species (type II). However, commonly all PDT drugs are oxygen-dependent, this therapy does not work in the anoxia region of the infected organ.

Near-infrared radiation has been widely applied to produce thermal spots and serve the resolution. Compared to other techniques, PTT has a great attraction to offer excellent therapeutic value because of its low invasiveness, enhanced therapeutic efficiency, low side effects, no need for long-lasting therapy, and fast recovery [38]. A photothermal agent can be allowed in the tumor microenvironment region and absorb the NIR laser lights to generate kinetic energy that releases thermal energy on the cancer cells and lead to cell death [39]. The permitted capacity of NIR absorption on healthy organs in the wavelength between 650–1350 nm develops crucial interpenetration in the patient’s body and destroys the tumors [40]. Additionally, this technique develops thermal waves to generate trouble in the cell membrane of the adjacent cancer cells [41]. Hyperthermia via absorption of NIR laser develops some problems such as short inter-penetrating power and strong absorption which leads to developing injury on normal cells and reducing the therapeutic efficiency. In the case of surface plasma resonances holding nanostructures, showed the electrons on the conduction band were localized on the surface of the nanomaterials upon NIR applications, and subsequently the localization attaints the target at the resonant frequency to develop resonances, thereafter absorbed NIR transforming into thermal waves. Therefore, it is probable to control NPS via local intravenous injection and consequently, exciting them in the NIR open windows I and II. Additionally, the nanomaterials incline to deposits in the spleen, kidney, and liver inducing injury irreversibly [42,43]. Hence, it is very essential to develop the PTT approach more safely and effectively.

Inorganic nanomaterials have more potential properties than organic nanomaterials due to colloidal stability, ease of synthesis in various adjustable sizes, and optical, magnetic, and quick surface modifications make them biocompatible materials in the area of biomedical applications [44,45]. Moreover, organic-based nanoparticles showed a higher degradation rate when compared to inorganic nanomaterials, this advantage makes them more colloidal stable in physiological conditions [46]. Among several types of inorganic nanoparticles, GNPs are promising candidates for photo therapies, due to their bioinertness, low cytotoxicity, as well as ease of preparation, and surface modifications [47]. Additionally, gold nanostructures are capable to improve the passive cellular uptake of phototherapies carriers in cancer sites through the enhanced permeability and retention (EPR) effect [48,49]. Further, GNPs hold a great surface area, which can aid in quick surface modifications with different bioactive molecules for active targeting in cancer therapy [50]. With the high binding affinity of GNPs with thiol and amine groups, the surface of GNPs can be modified with nucleic acids, proteins, and antibodies, which enable specific targeting ability and improve PSs delivery in tumor microenvironments [51]. The photostability of the GNPs leads to the high efficiency of absorbed laser radiation to thermal conversion which is photothermal conversion efficiency. The most important characteristics of GNPs is optical property originating from the localized surface plasmon resonance (LSPR) and huge surface-to-volume ratio that permits bioconjugation to bioactive molecules by a combination of various strategies of surface chemistry leads to develop conjugation of anticancer drug, targeting agent, and imaging probe in single nanoplatform [52]. In 1857, first time Faraday reported the synthesis of a colloidal solution of GNPs from the reduction of gold chloride (AuCl₄) by phosphorus [44]. Turkevich and co-authors reported the colloidal GNPs through the chemical reduction of gold salt with trisodium citrate [53]. Currently, apart from spherical GNPs, various types of gold nanostructures of different morphology have been reported, such as nanoshells, nanostars, nanorods, and nanocages [54,55,56,57]. The LSPR indicates the coherent oscillation of excited electrons from the surface of the metals by absorbing strong NIR radiation [54]. The rise of this oscillation increased absorption of the electromagnetic radiation in the combination of SPR of the metallic nanomaterials, which is estimated by the morphology and size of the nanostructures.

The optical properties of metal nanomaterials have been extensively used in nanomedicine, from real-time molecular imaging to multimodal therapeutic based on the use of light, for instance, gaining from the efficient light to thermal conversion gold nanostructures [58]. One major issue that was raised on the usage of nanomaterials in clinical practice is the potential cytotoxicity of these nanoparticles. Many nanoparticles have been shown to indicate cytotoxicity for both cancer and healthy cells, because of oxidative stress and the stimulation of inflammatory effects [58,59,60,61]. These cytotoxicity effects are commonly based on the structure and size of the nanomaterials [62]. The GNPs with sizes ranging from 20–60 nm showed low cytotoxicity for biomedical applications. Their use has been progressively permitted by regulatory frameworks advanced by the Federal Food and Drug Administration [63,64]. Moreover, surface charge shows a strong influence on acute cytotoxicity, in GNPs with positive charges showed much more toxicity to tissues when compared to negatively charged nanomaterials [65,66]. Currently, GNPs are extensively applied in biomedical science, particularly in molecular diagnosis, biosensing, nanocarrier for drug delivery, and phototherapy agents owing to their electronic, optical, and colloidal stability. In presence of LSPR, GNPs may be suitable for therapy depending on the variety of wavelengths in the NIR, adapting them for nanomedicine as carriers in PDT or photothermal agents in cancer phototherapy. Indeed, when GNPs are treated by NIR laser radiation, most often in the NIR region (650–900 nm), they appear to be effective in converting photons to thermal waves. When GNPs are irradiated, they will scatter thermal waves in a localized path, generating an effective flow in temperature (40–42 °C), which sequentially has a deep influence on the survival of cancer cells that are lowly resistant to localized thermal waves when compared to healthy cells. From these results, hyperthermia has been suggested as a unique non-invasive cancer theranostics with localized thermal effects and without side effects to healthy tissues or cells. Many light sources have been suggested, from radiofrequency to laser are applied to stimulate the irradiation in gold nanostructures for phototherapy [67,68,69,70,71,72].

The optical properties of gold nanostructures differ from other metallic nanomaterials. When gold nanostructures are treated with light, the excited electrons from the GNPs surface generated coherent oscillations which are named LSPR [73]. Due to this LSPR, deep amplified and localized electromagnetic fields are produced in the gold nanostructure surface upon irradiation with a suitable wavelength of the laser. The absorbed NIR radiation by GNPs would decay radiatively by dispersing the emitting light with the same wavelength as the incident light, meanwhile the nonradiative relaxation, potentially the delivery of localized thermal energy. Hence, GNPs concentrate the orders of magnitude optical absorption, which in turn open the window for using the gold nanostructures as various bioimaging and biosensing agent beyond photo-associated therapies. As LSPR is influenced by the density and motion of electrons on the GNPs surface, the distinct size and variety of morphology of gold nanostructures depend on their scattering and plasmonic absorption. Gold nanostructures are commonly prepared through the reduction of gold salt using various reducing agents, and suitable reaction methodology has been widely applied to attain different sizes and shapes. Gold nanorods, nanoshells, nanocages, and nanorings have been widely studied as promising candidates for phototherapy. Based on biomedical applications, the NIR ranging from 750 to 1700 nm is better for tissue penetration because of low tissue scattering. Especially, the radiation ranging from 1000 to 1350 nm (second NIR window) can penetrate deepest than the range from 750 to 1000 nm (first NIR window). However, very low assessable biocompatible probes exist for pre-clinical applications in the NIR window. Incidentally, the probability of shifting the laser absorption and the plasmonic band of gold nanostructures from visible to NIR region by tuning their sizes and varying the shapes makes them hopeful replacements for in vivo applications in the phototherapy of cancer [21]. Currently, the appreciation of translation of LSPR within the suitable NIR region from anisotropic gold nanostructures has stimulated the preparation of a variety of gold nanostructures such as gold nanoclusters, nanostars, and nanoplates. Among many, certain common functional groups are associated with the gold nanostructures to attain favorable multi-functionality for cancer theranostics. Advanced nanotechnology area provides the chance to build GNPs of different sizes and morphology.

The physicochemical characteristics of GNPs differ among various functionalization and these characteristics could be accurately regulated through nanotechnology with the drive of connecting interdisciplinary fields (chemistry, biological, and physical) needs of the multifunctional phototherapies.

Each of these gold nanostructures of various shapes holds certain special natures and their feature change openly depending on any rule. Important features of phototherapies, for instance, NIR absorbance and clearance rate, are majorly based on the shapes and sizes of these gold nanostructures. Materials science scientists must conduct various investigations to analyze the properties of these gold nanostructures to find those GNPs holds most desirable for phototherapies. Commonly, for a specific type of GNPs, the maximum extinction wavelength (λmax) increases with the increasing size of the gold nanostructures. GNPs with smaller sizes exhibit much better absorption capacity and a minimum scattering-to-absorption efficacy ratio. Hence, the GNPs have larger size that exhibits higher scattering efficiency. In this regard, large-sized GNPs are recommended for good resolution and sensitive imaging-guided phototherapies in cancer and small-sized GNPs have higher absorption capability that is suggested for good photothermal conversion efficiency in phototherapies. Determined maximum wavelength (λmax) and the ratio of scattering efficiency (µs) to absorption efficiency (µa) for GNPs with various shapes and sizes [74,75].

Over the past many eras, ongoing efforts have been made toward achieving an optimum association of nanoparticles and hyperthermia to overwhelm the issues of conventional thermal therapies. Among several reported nanoparticles for phototherapies applications, GNPs have been widely studied because of their high photothermal conversion efficiency and rapid surface modifications for improved targeted delivery of PS [79]. Plasmon resonance is a combined motion of a more number of mobile electrons [80,81,82]. In nanoparticle-mediated hyperthermia, GNPs can absorb strong NIR radiation and then produce the primary source of heat and reverse the direction of heat loss to stimulate thermal ablation on tumor cell [83,84,85,86]. Currently, various gold nanostructures have been translated for clinical trials, potential struggle has resulted in the reports of multiple research works on gold-based phototherapies in the recent literature such as gold nanocages, nanobipyramids, nanoflowers, nanoshell, nanorods, hollow nanospheres, nanostars, nanoechius and plasmonic blackbodies [87,88,89,90,91,92,93,94,95,96,97,98,99,100,101]. However, significant translations of these nanomaterials to pre-clinical trials have not yet been attained. The potential clinical trial on phototherapies is mostly based on irradiation duration, gross irradiation dose, and mode of radiation delivery. Moreover, traditional passive targeting phototherapies based on gold nanostructures have been circumscribed in clinical trials because of their non-specific ability and generate side effects on normal tissues. Hence, currently designing active targeting GNPs-based phototherapies are under clinical trials.

Even though the PDT has significant efficiency for cancer therapy, still it’s mainly limited to in vivo investigations and loss-efficient translation into the clinical trial [110]. In this regard, nanomaterials conjugated PS-based PDT has developed as a modern approach in which nanoparticles act as carriers for PS gaining from the special properties that generate them as PS themselves [111]. Various chemotherapeutic agents have been delivered by functionalizing the surface of GNPs. Thus, GNPs have aided the specific-targeted delivery to cancer sites of different biomolecules utilized as therapeutic agents. PS-conjugated GNPs result in significantly increased electron transfer between the gold nanostructure and the photoactive dyes which improves the photodynamic efficiency [112]. Up to date only a few of these gold-conjugated PS-mediated PDT nanoplatforms achieved clinical trials. Recently, Anine Crous reported the application of AuNPs as a carrier for the AlPcS₄Cl PS. In this study, synthesized gold nanoparticles were conjugated AlPcS₄Cl, and in vitro models revealed that phototherapy using the AlPcS₄Cl-gold nano bioconjugate was potential against human lung (A549) cancer cells [113]. In another approach, specific targeted PDT was carried out with folic acid (FA) and protoporphyrin IX (PPIX) conjugation on surface-modified AuNPs. The authors initially applied 6-mercapto-1-hexanol (MH) on the surface of AuNPs and it enhances the bioconjugation of FA/PPIX on nanoparticles to form a nanosystem (PPIX/FA-MH-AuNP). In this study, the synthesized nanosystem showed high cytotoxicity against HeLa cancer cells, due to the presence of targeting ligands FA and folate-mediated endocytosis. The results show that the PPIX/FA-MH-AuNP nanosystem increases the targeting nature and also phototoxicity efficiency of HeLa cells when compared with the traditional PDT [114]. In another approach, gold-based core@shell nanostructure was utilized to conjugate with PS for effective PDT. Ping and co-authors developed the nanosystem of Au@TiO₂ nanostructure with hematoporphyrin monomethyl ether (HMME). The PDT efficiency of Au@TiO₂-HMME was studied in KB cancer cells [115]. Dimakatso and co-authors fabricated the physically loaded hypericin (Hyp) on gold nanoparticles through sonication. The non-covalent bonds between the AuNPs and Hyp increase the PS accumulation in MCF-7 breast cancer cells and hence improve PDT efficiency with the minimum concentrations. From this study, it is revealed that physically loaded Hyp PS on AuNPs is a hopeful strategy for hydrophobic PS drug delivery to improve PDT efficiency [116]. 

Hypoxia commonly exists in the tumor microenvironment due to the excess proliferation of cancer cells that surpass the blood circulation and oxygen supply for the growth of weak vasculature tumors. It has been revealed that hypoxic efficiently promotes cancer development and invasion [126]. The potentiality of PDT is restricted by hypoxia since the traditional PDT is oxygen dependent to generate reactive oxygen species (ROS). Hence, targeting hypoxia in the tumor sites in absence of oxygen-based PDT has developed as a potential tool to enhance PDT. A recent review by Lou-Franco reported that gold nanostructures hold efficient enzymatic activities for instance reductase, peroxidase, oxidase, and superoxide dismutase, which can be leveraged to relieve hypoxia [127]. In a recent study, an oxygen self-producing nanosystem containing metal-organic frameworks, AuNPs and Ce6 PS was utilized to diminish the hypoxic which consequently improves PDT. In this approach, AuNPs are applied to catalase efficiently by catalyzing the high H₂O₂ developed in the tumor sites to generate oxygen molecules to reduce hypoxia and improve ROS generation with high cytotoxicity [128]. Moreover, to reduce hypoxia and improve PDT, core@shell Au@Rh nanoparticles based on Au and rhodium (Rh) with catalase activities were applied as nanoenzyme. The ICG was conjugated with Au@Rh and functionalized with a cancer cell membrane (CM) to develop Au@Rh-ICG-CM nanosystem. The nanosystem catalyzed the H₂O₂ in the tumor sites to form oxygen via the action of Au@Rh to improve ROS generation for efficient PDT. The functionalization with CM permits specific targeting via homology adsorption [129].

In a very recent study, Yin and co-authors reported gold nanoclusters (AuNCs), mesoporous silica (mSiO₂), and MnO₂-based nanoenzyme system with oxygen generators for improved PDT and magnetic resonance imaging. In this study, the nanosystem made up of AuNCs doped on mSiO₂ was coated with MnO₂ and acted as a shell (AuNCs@mSiO₂@MnO₂). In lower pH, becomes turn ‘on’ the nanoenzyme is treated with H₂O₂ consequently resulting in the degradation of MnO₂. The slow degradation of MnO₂ generates massive oxygen molecules, which in turn enhances Magnetic Resonance Imaging and PDT [131].

The boundaries of cancer nanotheranostics are constantly being altered as better thought of biomedical characteristics of nanomaterials is expanding. Over the last two decades, there is an outstanding evolution in the fabrication and advantages of various nanostructures in cancer nanotheranostics [132]. In this regard, GNPs have currently emerged as the most hopeful theranostic agent [133,134]. The gold nanostructures are the potential ability for passive accumulation and preferentially reach the tumor microenvironment through enhanced permeability and retention effect of the infected organs [135]. In addition to that, the surface of gold nanostructures can be readily modified with biomolecules such as peptides, monoclonal antibodies, and proteins to overcome the non-specific targeting ability of theranostics agents [136,137,138,139]. Due to their natural biointerness, surface area-to-volume ratio, and surface chemistry, gold nanostructures are widely applied as nanocarriers for targeted drug delivery [140]. The high atomic numbers in gold are capable to afford a higher X-ray absorption cross-section, making them promising nanomaterials to act as potential radiosensitizers for improving radiotherapy (RT) [141]. Moreover, the photothermal conversion efficiency of gold nanostructures can be used to produce localized thermal for tumor ablation [142]. In recent years, the thermal efficiency of gold nanomaterials has been discovered and utilized to help hyperthermia in curing cancer. According to this, the radiofrequency (RF) electrical field absorption efficiency of gold nanostructure combined with their sonosensitizing characteristics has been employed to enhance the RF and ultrasound-stimulated hyperthermia therapeutic efficiency [143]. In addition to these, the thermal efficiency of gold nanostructures can be applied to stimulate responsive drug payload delivery with good specific and resolution upon external triggering through hyperthermia materials [144,145]. Currently, many biomaterials scientists have also revealed that gold nanostructures are capable to produce cytotoxic ROS upon laser and ultrasound treatments, and could therefore be applied to promote PDT and sonodynamic therapy simultaneously [146,147]. With these characteristics combined into a single nanoplatform, gold nanostructures have emerged as an entirely irreplaceable nanostructure ability to combine various therapies to attain improved therapeutic outcomes. Hence, they could deliver a golden choice to combine various therapies in a single mode, thus emphasizing the influence of gold nanostructure in synergetic cancer theranostics. Taking the benefit of gold nanostructures for real-time co-delivery of various therapies cannot only improve the potentiality of every individual cancer treatment but fascinatingly may also deliver an extra advantage by the synergistic interactions that happen among different therapies, which results in very powerful therapeutic outcomes. This synergistic therapy also aids to limits high dose concentrations and associated side effects by permitting a reduction in administered drugs level for cancer treatments [148]. Table 1, provides a summary of the therapeutic aids of various gold nanostructures for synergetic phototherapies for cancer theranostics.