Photoactive Nanomaterials Containing Metals for Biomedical Applications: A Comprehensive Literature Review

Abstract

This review summarizes recent advances in photoactive nanomaterials containing metals and their biomedical applications, particularly in cancer diagnosis and therapy. Conventional approaches such as chemotherapy and radiotherapy suffer from low specificity, systemic toxicity, and resistance, while light-based therapies, including photothermal therapy (PTT) and photodynamic therapy (PDT), offer minimally invasive and localized alternatives. Metal nanomaterials, especially gold and silver, exhibit unique localized surface plasmon resonance (LSPR) effects that enable efficient light-to-heat or light-to-reactive oxygen conversion, supporting precise tumor ablation, drug delivery, and imaging. We discuss strategies for structural design, surface functionalization, and encapsulation to enhance stability, targeting, and therapeutic efficiency. Emerging hybrid systems, such as carbon-based nanostructures and metal–organic frameworks, are also considered for their complementary properties. Computational modeling tools, including finite element and discrete dipole approximations, are highlighted for predicting nanomaterial performance and guiding rational design. Finally, we critically assess challenges such as toxicity, long-term biocompatibility, and clinical translation, and provide perspectives for future development. By integrating materials design, simulation, and preclinical findings, this review aims to inform the advancement of safer and more effective nanotechnology-based platforms for personalized cancer treatment and diagnosis.

1. Introduction

The prevention and treatment of diseases remain critical challenges in medical science, requiring continuous innovation in prevention, diagnosis, and therapy to address persistent obstacles. Recent advances in nanomedicine have enhanced the effectiveness of primary treatments while offering significant potential for managing recurrences and metastases. Conventional therapies face notable limitations. Radiotherapy often demonstrates limited efficacy due to tumor cell radio resistance [1], while chemotherapy’s low selectivity for cancer cells and narrow therapeutic window increases the risk of adverse effects on healthy tissues [2]. Furthermore, the tumor microenvironment (TME), characterized by hypoxia, mild acidity, and elevated H₂O₂ levels, can diminish therapeutic efficacy [3,4].

In response to these challenges, modalities, such as radiotherapy [5] and alternative light-based approaches, including photodynamic therapy (PDT) [6], photothermal therapy (PTT), and photoimmunotherapy (PIT) [7], have gained attention. Among these, PTT offers specific advantages, including high specificity, minimal invasiveness, and precise spatiotemporal control [8]. PTT not only inhibits metastasis, but also targets cancer stem cells resistant to conventional therapies, potentially disrupting cancer cell motility and reducing metastatic potential [9,10]. Preclinical studies have shown that combining PTT with chemotherapy or radiotherapy can enhance metastatic control and improve therapeutic outcomes [11]. PTT efficacy depends on parameters such as the heat-generating capacity of nanomaterials, their tumor selectivity, and laser irradiation conditions. This specificity arises mainly from the spatially confined delivery of near-infrared (NIR) light, which limits heating to the illuminated region, and from the preferential accumulation of photothermal agents within tumors through the enhanced permeability and retention (EPR) effect or active targeting. Therefore, the degree of selectivity strongly depends on the photothermal agent used, as its absorption profile, photothermal conversion efficiency, and biodistribution govern the extent of localized heat generation [12,13].

Recent progress has introduced ultrasmall-in-nano architectures as promising theranostic agents. In these systems, ultrasmall metallic nanoparticles (typically <5 nm) are assembled into biodegradable nanocapsules that retain NIR-responsive plasmonic resonance and efficient photothermal conversion while ensuring renal excretion of the released building blocks after disassembly. This design enables effective tumor accumulation and NIR imaging, while simultaneously providing excretable photothermal activity, thereby improving both safety and translational potential [14].

Functional photothermal nanomaterials (PTAs) offer multiple strategies for cancer therapy, including direct tumor ablation, image-guided selective irradiation, and combination therapies, as illustrated in Figure 1 [15,16]. Functional PTAs have proven to be valuable in molecular biomarker detection, medical imaging, and cancer treatment due to their exceptional optical properties, tissue penetration, and enhanced permeability and retention (EPR) effects [17]. Metallic nanostructures are particularly promising for PTAs because of their stability, ease of synthesis, and unique optical and electrical properties [16]. Their high surface-area-to-volume ratio, combined with EPR-mediated tumor accumulation, enhances treatment efficacy while minimizing harm to healthy tissues [17]. Functionalization with antibodies, small molecules, or aptamers further enables active targeting, improving nanoparticle internalization in cancer cells and enhancing therapeutic outcomes [18]. Among metallic PTAs, gold nanostructures are the most widely investigated due to their strong and tunable LSPR absorption in the NIR region, high photothermal conversion efficiency, and biocompatibility [15,17]. Silver nanoparticles also exhibit intense plasmonic responses, but require stabilization strategies to improve chemical stability, often achieved through Ag@Au hybrid designs [19]. Copper-based nanomaterials (such as Cu and Cu_2−xS) are attractive low-cost alternatives with efficient NIR absorption and promising biocompatibility [20]. In addition, palladium and platinum nanostructures are gaining interest for their high thermal stability and potential for combined photothermal and catalytic therapies [21,22]. However, concerns remain regarding their long-term biocompatibility and potential organ accumulation, which must be carefully considered for biomedical applications [23,24].

2. Physical Principles and Photothermal Mechanisms

For PTT and PDT, nanoparticles must exhibit high photostability, biocompatibility, and strong near-infrared (NIR) absorbance within the optimal phototherapeutic window (700–1100 nm), where tissue light attenuation is minimal. Noble metal nanoparticles, which naturally exhibit surface plasmon resonance absorption in the visible spectrum, can be engineered to shift absorption to the NIR range by modifying size, shape, or the surrounding dielectric medium [25]. Efficient excitation of localized surface plasmon resonance (LSPR) occurs when the wavelength of the incident light matches the oscillation frequency of conduction electrons, a condition strongly dependent on nanoparticle morphology and dielectric environment, which together determine the spectral position and absorption intensity [26,27,28]. Despite these advantages, the clinical translation of PTT faces challenges: fewer than 1% of administered nanomedicines reach tumor tissues, and plasma protein absorption can alter nanoparticle structure, reducing bioavailability and retention time [20]. Surface charge also plays a critical role in toxicity and biological interactions, necessitating appropriate coatings. Polymers such as PEG, poly(L-lactide-co-glycolide), polyvinylpyrrolidone, and dextran mitigate toxicity, prevent aggregation, and extend circulation time, while reducing protein corona formation that could impair therapeutic efficacy [29,30,31,32,33].

The application of functional nanomaterials in PTT and PDT presents a promising avenue in biomedicine. Understanding strategies for the morphological and structural control of nanoparticles is essential to optimizing their function in the tumor microenvironment. Overcoming challenges related to targeting, bioavailability, and stability is crucial for advancing these therapies toward clinical application.

2.1. Localized Surface Plasmon Resonance (LSPR) Fundamentals

Noble metal-based nanomaterials exhibit unique properties, including localized surface plasmon resonance (LSPR), which is activated upon laser excitation. LSPR refers to the collective oscillation of surface electrons in metal nanoparticles when exposed to light of a specific wavelength [34,35].

When light interacts with these nanomaterials, the electric field of the light polarizes free electrons on the nanoparticle surface, creating an exothermic electron gas. These electrons oscillate in resonance with the incident light’s frequency, leading to the accumulation of negative and positive charges on opposite regions of the nanoparticle surface. This energy is subsequently converted into heat through the Joule effect. The heat generated is transferred to the surrounding environment, causing a localized temperature increase in tumor tissues due to the relaxation of excited electrons [34,35,36], as depicted in Figure 2 [37].

2.2. Light-to-Heat Conversion and Tumor Ablation

This localized heating can induce apoptosis and necrosis in nearby cancer cells, establishing photothermal therapy (PTT) as a promising treatment strategy [38].

In hybrid systems, plasmonization occurs by incorporating materials that exhibit LSPR. However, materials with intrinsic plasmonic properties naturally display this effect. The efficiency of radiation-to-heat conversion depends on several factors, including nanoparticle concentration, the intensity and duration of near-infrared (NIR) laser irradiation, and the properties of the target tissue [39].

Enhancing conversion efficiency can be achieved by combining noble metals with other materials, such as silica, iron oxide, or small molecules like IR780 and ICG [38,39]. These combinations improve the photothermal response, offering greater control and effectiveness in therapeutic applications [38].

2.3. Mechanism of Cell Death Induced by Photothermal Therapy

PTAs are extensively utilized in PTT due to their high efficiency in converting light into heat, enabling the selective destruction of cancer cells. This conversion mechanism relies on the surface plasmon resonance (SPR) effect, which arises from the interaction between light and conduction band electrons in PTAs. The enhanced permeability and retention (EPR) effect facilitates the preferential accumulation of PTAs in tumor tissues. Upon NIR laser irradiation, the accumulated PTAs generate localized temperature increases, contributing to the targeted elimination of cancer cells, as illustrated in Figure 3, adapted from Taheri-Ledari et al. [11], who reported plasmonic Au/Ag porous micro- and nanostructures with efficient NIR absorption and promising photothermal performance for cancer therapy [38,40,41].

PTT involves the administration of PTAs to the lesion site using bioengineered carriers such as stem cells, microbubbles, or intravascular catheters. Upon activation by near-infrared (NIR) laser radiation, PTAs accumulate at the target site and produce heat through their photoabsorbent properties. This localized heating enhances vascular and cellular permeability, promoting the uptake of additional therapeutic agents. The generated heat can also induce protein denaturation and DNA damage, leading to cell death via necrosis or apoptosis. The specific mechanism of cell death is influenced by factors such as the properties of the photoabsorbent agent and the irradiation parameters [42].

An 808 nm laser, which lies within the first near-infrared (NIR) window (700–1100 nm), is commonly employed to achieve optimal tissue penetration while minimizing damage to surrounding healthy tissues [43,44]. Other NIR wavelengths, such as 980 nm and 1064 nm, are also frequently used depending on the absorption band of the photothermal agent [39].

3. Types of Photoactive Nanomaterials

Plasmonic noble metal-based organic and inorganic nanomaterials have seen significant advancements in medicine and related sciences. Metallic nanoparticles (NPs) are renowned for their unique optical, electrical, and magnetic properties, stemming from a high surface-to-volume ratio. These properties, coupled with their therapeutic potential, make localized surface plasmon resonance LSPR-active nanomaterials ideal for theranostic applications, bioimaging, and biosensor technologies.

Biomedical applications such as bioimaging, targeted therapy, PTT, and PDT benefit from nanoparticles smaller than 100 nm, which interact with a broad spectrum of light wavelengths, enabling absorption and emission beyond the red band. Noble metals like gold (Au) and silver (Ag) exhibit plasmon resonance in the visible and near-infrared (NIR) regions. The efficiency of LSPR-active materials depends on their composition, particle size, shape, dielectric environment, and interparticle interactions [28]. While other metals, such as platinum and palladium, also possess plasmonic properties, high costs and low in vivo degradability limit their clinical application [45].

3.1. Noble Metal Nanoparticles (Au and Ag)

Silver nanoparticles (AgNPs) are valued for their straightforward synthesis, high thermal conductivity, chemical stability, antibacterial properties, size-dependent physicochemical traits, and moderate biocompatibility. AgNPs leverage SPR for applications in imaging and PTT. Smaller AgNPs exhibit fluorescence near the Fermi wavelength, while larger particles show SPR [46]. AgNPs also demonstrate cytotoxic and genotoxic effects on cancer cells. Compared to AuNPs, AgNPs have stronger plasmon resonance, enhancing their potential in medical applications. Nevertheless, their biomedical use requires stabilization strategies or hybrid designs to improve chemical stability, circulation, and biocompatibility [46,47].

Gold nanoparticles (AuNPs) are among the most studied inorganic materials in biomedicine due to their optical absorption properties, biocompatibility, high surface area, and inert nature [8,48,49,50]. AuNPs efficiently accumulate in tumor tissues, enabling the thermal ablation of cancer cells when irradiated with an external light source. Moreover, they can induce immunological responses by releasing damage-associated molecular patterns (DAMPs) that stimulate antitumor immunity. Their stability, non-toxicity, and versatile optical properties make them effective in PTT for treating superficial tumors and skin cancers, particularly when combined with NIR laser irradiation [8]. AuNPs also serve as contrast agents in computed tomography (CT) and magnetic resonance imaging (MRI).

Despite these benefits, AuNPs present challenges, such as potential cytotoxicity from nonspecific biomolecular interactions during circulation, limited loading capacity for hydrophilic drugs, and risks of organ accumulation due to small particle sizes. In biomedical applications, AuNPs are most employed in the 10–100 nm range, which offers a balance between tumor accumulation and clearance. Nevertheless, their safety remains controversial: while many studies demonstrate good biocompatibility, others report long-term retention in organs and cytotoxic effects depending on particle size, surface chemistry, and dosage [32,33,49]. As summarized in Figure 4, various morphologies such as nanospheres, nanorods, nanotriangles, nanocages, and nanoshells [49] demonstrate different cellular uptake behaviors and PTT efficiencies [34,35]. In addition to morphological variety, Figure 4 also includes different compositions such as core–shell and hybrid nanostructures, which have been designed to improve optical performance, stability, and therapeutic efficacy. Naked AuNPs are rarely employed in biomedical applications, as functionalization or hybridization is generally required to enhance biocompatibility, circulation stability, and tumor selectivity while reducing potential toxicity [38,49,51]. For example, gold nanostars (AuNSTs) demonstrate broad SPR spectra and superior heat generation, with lower cytotoxicity and higher cellular uptake compared to other forms. Surface functionalization improves biodistribution, enabling targeted delivery and reducing potential harm to healthy tissues [52].

However, AuNPs face challenges such as weak optical signals, long-term cytotoxicity, and reduced therapeutic efficiency. Factors like size, administration route, dosage, and physiological interactions influence toxicity.

To model the optical properties of different nanoparticle geometries, the discrete dipole approximation (DDA) is employed. This method discretizes nanoparticles into polarizable points, where dipole moments are influenced by incident light and interactions with neighboring dipoles. Figure 5 illustrates how DDA simulations demonstrate the significant influence of nanostructure shape on optical properties. Structures with sharp corners, such as tetrahedra, exhibit red-shifted resonance peaks due to enhanced charge separation. Similarly, hollow nanostructures, like nanoshells, display progressive red shifts as wall thickness decreases.

In general, nanostructures with lower symmetry exhibit a greater number of resonance modes, while red shifts become more pronounced with increasing anisotropy, sharper corners, and thinner walls. The intensity of these resonance peaks is dictated by the symmetry of dipole moments. Understanding these principles provides a framework for designing metal nanostructures with tailored optical properties, optimizing their application in PTT and other biomedical technologies [66].

da Silva et al. (2022) [26] compared the catalytic performance of Au@AgAu nanorattles (~90 nm) with AgAu nanoshells (~80 nm) and conventional Au nanoparticles (~25 nm) under identical loading conditions. The results showed that the nanorattles exhibited significantly enhanced catalytic activity, achieving over 90% aniline conversion within 10 h. This performance represents an approximately threefold increase compared to the combined efficiency of the reference nanostructures. Superior activity is attributed to efficient plasmon hybridization within the nanorattles, which enhances light absorption and intensifies local electromagnetic fields [26,67].

Pakravan et al. (2021) [68] examined the influence of various gold nanoparticle (AuNPs) geometries on cellular uptake and photothermal therapy (PTT) efficacy in eliminating MCF-7 breast cancer cells. The researchers synthesized seven distinct anisotropic GNPs: gold nanospheres (AuNSPs ~20 nm), nanorods (AuNRs ~40 × 10 nm), nanocages (AuNCs ~50 nm), nanostars (AuNSTs ~70 nm tip-to-tip), hollow nanospheres (HAuNPs ~60 nm), Fe₃O₄/Au core–shell nanoparticles (FeAuNShs ~90 nm), and SiO₂/Au core–shell nanoparticles (SiAuNShs ~100 nm) [68]. Using ICP-MS and flow cytometry, they assessed how geometry affected cellular uptake, while PTT efficacy was evaluated through MTT assays, cell cycle analysis, and annexin-V apoptosis assays in vitro. These results confirm that not only geometry, but also particle size strongly determines uptake, cytotoxicity, and PTT efficacy, with nanostars (~70 nm) offering an optimal balance between heating capacity and biocompatibility.

The study revealed that all AuNPs were effective in absorbing light and converting it into heat. Among them, gold nanostars showed the most promising characteristics, including lower cytotoxicity, higher cellular uptake, and superior heat generation. These nanostars exhibited a broad surface plasmon resonance (SPR) spectrum peaking around 800 nm, while core–shell nanoparticles (HAuNPs, FeAuNShs, and SiAuNShs) demonstrated absorption peaks in the near-infrared region. The findings indicated that the geometry of AuNPs significantly impacts cellular uptake, heat production, and apoptosis induction, with gold nanostars emerging as particularly effective in PTT applications. AuNRs coated with CTAB exhibited high cytotoxicity, but substituting CTAB with BSA reduced toxicity. Similarly, PVP-coated HAuNPs and AuNCs displayed mild toxicity, while AuNSTs, AuNSPs, FeAuNShs, and SiAuNShs exhibited negligible cytotoxicity. AuNSTs were notably effective, achieving a temperature increase to 53 °C and a 79.67% cell death rate after 10 min of irradiation. Conversely, Fe-Au and Si-Au core–shell nanoparticles showed reduced cellular uptake due to electrostatic repulsion. Overall, the study underscored the critical role of shape and morphology in determining the cytotoxicity and therapeutic potential of AuNPs, with gold nanostars standing out as the most promising candidates for PTT.

Yang et al. (2021) [69] synthesized three commonly used gold nanostructures—nanospheres (AuNSs ~30 nm), nanorods (AuNRs ~50 × 15 nm), and nanostars (AuNSTs ~60–80 nm)—functionalized with identical mPEG-SH surface modifications to compare their photothermal conversion efficiency and suitability as photothermal agents (PTAs) in prostate cancer cells (PC-3) under 808 nm laser irradiation at 300 mW/cm². All AuNPs exhibited surface plasmon resonance (LSPR) effects, with AuNSTs showing the highest photothermal conversion efficiency and a prominent absorption peak around 520 nm [69]. The comparative design highlighted the size-dependent nature of photothermal conversion, with larger nanostars outperforming smaller nanospheres.

In vitro cell tests demonstrated that all pegylated AuNPs had low cytotoxicity, with AuNSTs inducing local hyperthermia most efficiently, achieving a 13.4 °C temperature increase after 10 min of 808 nm irradiation. Surface modification with mPEG-SH enhanced the stability and biocompatibility of AuNPs without significantly altering their morphology or optical properties. The addition of coating agents, such as CTAB for AuNRs and dehydroascorbic acid for AuNSTs, further improved the stability of the PTAs. Only cells treated with AuNRs at a high concentration (200 μg/mL) showed observable cytotoxicity, likely due to residual CTAB surfactant. At the same concentration, AuNSTs demonstrated the most effective anti-tumor effect, with only 30% of PC-3 cells surviving after 10 min of irradiation.

The results highlight AuNSTs as the most promising PTAs due to their efficient photothermal conversion and ability to induce localized hyperthermia. These findings also suggest that the distinct morphologies of AuNPs confer unique characteristics suitable for various PTT applications.

In photothermal therapy (PTT), AuNRs are extensively studied for their tunable plasmon resonance, adjustable via aspect ratio [70]. AuNRs typically exhibit a weak absorption band in the visible region and a strong band in the near-infrared (NIR) region. They are synthesized using a seed-mediated growth method with CTAB as a surfactant to prevent aggregation. In vivo tests indicate that AuNRs do not interfere with vital organ functions, though surfactant-related toxicity remains a challenge despite mitigation efforts.

DMBA, a polycyclic aromatic hydrocarbon, induces mammary tumors in rats. PTT activates photosensitizers to generate reactive oxygen species, leading to tumor destruction. AuNRs exhibit favorable optical and electronic properties for PTT. Coating AuNRs with polyvinylpyrrolidone (PVP) enables targeted drug delivery, reducing off-target effects, toxicity, and improving colloidal stability. Gamal et al. (2023) evaluated PTT efficacy using PVP-coated AuNRs (~45 × 12 nm) in a DMBA-induced rat breast cancer model [71]. Wistar rats treated with PVP-AuNRs and subjected to 808 nm NIR laser irradiation showed a >75% tumor volume reduction compared to untreated groups. PVP coating improved dispersion and stability over CTAB-coated AuNRs. TEM images confirmed selective destruction of breast cancer cells, demonstrating significant therapeutic potential. This work emphasized that maintaining a controlled aspect ratio is crucial for maximizing tumor ablation while reducing systemic toxicity.

Cui et al. (2023) [53] synthesized Au/Ag core–shell nanorods (Au/Ag NRs ~60 × 15 nm) with strong NIR-II photoabsorption for catalytic cancer therapy. Their defined dimensions were directly correlated with SPR tuning to 1071 nm and enhanced catalytic activity. Au/Ag NRs exhibited peroxidase activity, catalyzing H₂O₂ into hydroxyl radicals to induce cancer cell death. Their pronounced NIR-II photothermal effect synergized catalytic and PTT effects, enhancing cancer inhibition in vitro and in vivo. DSPE-PEG-SH coating improved biocompatibility, colloidal stability, and dispersion, shifting the SPR peak to 1071 nm with a 26.1% photothermal conversion efficiency. Histological analyses revealed no tissue damage, underscoring their potential for CT imaging-guided oncotherapy [53].

Gold nanoagglomerates are formed by coupling or aggregating ultrasmall spheres (<10 nm) into clusters >100 nm via polymeric spacers, dendrimers, or organic molecules. These findings illustrate that aggregation into larger assemblies enhances optical cross-sections, but compromises renal clearance. For example, Chegel et al. (2012) reported that amine- and thiol-containing compounds promoted citrate-coated AuNP aggregation [72]. Park et al. (2019) used albumin to form gold nanoclusters for photothermal colon cancer treatment, achieving 70 °C under 808 nm irradiation, suppressing tumor growth without major organ damage [73]. Similarly, Iodice et al. (2016) employed PLGA-based molecules for aggregation, raising temperatures by 20 °C, effectively targeting breast cancer cells and glioblastoma spheroids [74]. Li et al. (2017) crosslinked peptide-modified AuNPs with 1,9-nonanediol, achieving nearly complete pancreatic tumor eradication when combined with photodynamic agents [75].

Hollow, porous nanostructures like nanocages (~40–60 nm) [76] exhibit exceptional optical properties for combinatorial cancer therapies. The tunable shell thickness and cavity size directly influenced absorption shifts in the NIR range and drug release profiles. Galvanic reduction processes involving Ag nanocubes yield porous Au cages. Panfilova et al. (2012) showed tunable LSPR peaks based on Au layer thickness and Ag/Au ratios, optimizing NIR absorption [77]. Cheng et al. (2018) utilized Au nanocages for lung cancer therapy, achieving controlled drug release and reducing cell viability under 808 nm irradiation [78].

Gold nanostars (AuNSTs ~50–80 nm), synthesized via seed-mediated methods [79], feature enhanced surface area and NIR absorption. Tip length and overall size strongly dictated both absorption profiles and therapeutic efficiency. Their LSPR properties depend on core and tip morphology. For instance. For instance, Yuan et al. (2012) demonstrated that higher Ag⁺ concentrations increased tips, enhancing heat generation [80]. As a purely Au-based example, Li et al. (2016) coated AuNSTs with polydopamine (PDA) for cervical cancer PTT, achieving complete tumor ablation [81]. Similarly, Wang et al. (2013) functionalized AuNSTs with Chlorin e6-PEG for breast cancer treatment [82], while Nam et al. (2018) combined PDA and doxorubicin for colon carcinoma therapy, achieving tumor regression in 40% of cases [83]. Nevertheless, despite their promising performance, safety concerns remain regarding long-term biodistribution, clearance, and possible organ accumulation of AuNSTs, which highlight the need for further in vivo studies.

Following the promising results of Au nanostars, other anisotropic morphologies such as gold nanocages (AuNCs, 30–70 nm) also demonstrate superior photothermal properties and stability, enabling temperature-activated drug release in combined therapies [84]. These dimensions ensure strong NIR absorption while allowing for partial clearance when below ~50 nm. Optimizing size, shape, and porosity enhances their therapeutic potential. Advances in synthesis and functionalization continue to improve their clinical applications, with structures like nano-rings and hollow nanospheres facilitating renal excretion post-therapy, ideal for theranostics [26]. Ongoing innovations will further enhance nanostructure-based cancer therapies.

3.2. Core@Shell Nanostructures

Core@shell nanomaterials are highly valued for their adjustable multifunctional properties, derived from the combination of multiple phases at the nanoscale [38,56,85,86]. These nanoparticles consist of a core and a shell, both nanoscale components, whose interactions significantly enhance material performance [40]. They are typically synthesized using approaches such as seed-mediated growth, galvanic replacement, and co-reduction, which enable precise control over particle size (generally in the 20–100 nm range) and shell thickness [41]. Compared with alloyed bimetallic nanoparticles, core@shell structures provide superior structural stability, enhanced optical tunability, and the ability to independently tailor the functionality of the core and the shell [49]. Among them, Au@Ag core@shell structures have gained attention for their strong plasmonic response coupled with the chemical stability and biocompatibility conferred by the Au shell, while Ag@Au structures show even higher plasmonic activity, but are more prone to oxidation and cytotoxicity. These features make core@shell nanostructures highly relevant in biotechnology, biochemistry, biophysics, and biosensing [85,87].

In biomedicine, core@shell nanomaterials are widely studied due to their unique optical, electrical, and magnetic properties, along with their low toxicity, high surface area, enhanced conjugation with bioactive molecules, biocompatibility, and selectivity for target molecules. As illustrated in Figure 6, these properties can be fine-tuned by modifying the core-to-shell ratio and altering the chemical composition of the nanomaterials [88,89].

For instance, Shiju E. et al. (2021) investigated the nonlinear optical properties of Au@Ag core–shell nanostructures, observing a surface plasmon resonance shift from 519 nm to 411 nm with the formation of the silver layer [40]. The linear optical properties of these nanostructures were tunable by varying the Ag shell thickness. Enhanced nonlinear optical properties were attributed to increased local field and scattering effects. The extinction cross-sections of these nanostructures were significantly larger than those of pure Au nanoparticles, increasing with greater Ag shell thickness. Additionally, the materials exhibited negative nonlinearity in refractive properties, highlighting their potential in nonlinear optics.

In another study, Au@Ag nanoparticles synthesized using Rumex hymenosepalus root extract as a reducing agent had an average diameter of approximately 250 nm and good polydispersity (PDI ~0.2), making them suitable for biological applications [92]. These findings suggest that bimetallic Au@Ag nanoparticles synthesized via green methods hold promise for biomedical applications, particularly in photothermal cancer treatment.

Sullivan et al. (2018) synthesized bimetallic Ag@Au nanoparticles using a green synthesis route with aqueous chloroauric acid (HAuCl₄), silver nitrate (AgNO₃), and Acacia nilotica bark extract as reducing and coating agents [93]. The nanoparticles exhibited surface plasmon resonance (SPR) in the visible region, peaking between 400 and 600 nm. Their anticancer activity was tested against HeLa cervical carcinoma cells, showing decreased LSPR band intensity with increased shell thickness. The anticancer activity and behavior in biological fluids were linked to their structure, size, shape, and distribution [94].

Cytotoxic tests revealed significant toxicity of Ag@Au nanoparticles against HeLa cells, possibly due to nanoparticle internalization, which ruptures cells and releases silver nanoparticles, enhancing toxicity [95,96]. Oxidative stress caused by free radicals, disruption of the mitochondrial electron transport chain, and endocytosis also contribute to this toxicity. These findings underscore the potential of these nanoparticles in cancer therapies and other pharmaceutical and nanomedicine applications. It should be noted that cytotoxicity was only assessed in cancer cells, and additional studies using healthy cell models are necessary to fully establish their biocompatibility and safety profile.

Silva-Silva et al. (2023) employed green synthesis [90] to prepare bimetallic Ag@AuNPs using Hymenaea courbaril (Jatobá) leaf extract as a reducing and stabilizing agent. The SPR band ranged from 433 nm for pure AgNPs to 508 nm for Ag@AuNPs with a higher gold proportion, confirming the formation of a core–shell structure. The zeta potential ranged from −19.5 mV to −12.4 mV, indicating good electrostatic stability, likely due to biomolecule adsorption from the extract onto the nanoparticle surface. The thermo-optical properties of Ag@AuNPs demonstrated that varying the gold-to-silver ratio affects the thermal lens signal magnitude, showing the tunability of these properties by adjusting metallic precursor ratios [90].

Additionally, thermal diffusivity and nonlinear absorption increased with higher gold content in the silver core. Characterization confirmed their structural and stability properties. Ag@Au NPs exhibited nonlinear optical properties, suggesting applications in nonlinear and photothermal optics. This study highlights green synthesis as a sustainable and innovative method for producing metallic nanoparticles.

3.3. Metal–Organic Frameworks (MOFs)

Figure 7 presents the classification of transduction nanoagents into organic, inorganic, and hybrid PTAs, reflecting their structural composition and functional versatility for biomedical applications.

Among these hybrid materials, Metal–Organic Frameworks (MOFs) stand out as porous, crystalline organic-inorganic composites that serve as excellent support layers for embedded plasmonic materials, protecting them from rapid degradation in blood serum. Furthermore, the outer surface of MOFs can be conjugated with biologically active molecules to induce selective functionalities [11,98]. Their inherent porosity makes MOFs ideal hosts for depositing plasmonic materials as well as co-therapeutic agents, enhancing their applicability in cancer treatment.

In MOF research, pores larger than 2 nm are particularly important. Hierarchical porous MOFs (HP-MOFs) combine micropore functionality with high surface area and mesopores/macropores within the microporous matrix. This structure accommodates larger species and reduces diffusion barriers [99].

Porous silica is another desirable host platform for plasmonic materials due to its high surface-to-volume ratio, ease of synthesis, and capacity to regulate pore size. Combined with chemical inertness, stability, selectivity, and biocompatibility, silica is an excellent catalytic support. For example, silica enhances the colloidal stability and drug-loading capacity of gold nanostructures without affecting NIR excitation, though it may alter AuNP optical properties, potentially enhancing photoluminescence.

A silica shell on AuNPs optimizes localized surface plasmon resonance (LSPR) properties while increasing thermal stability and protecting against photodegradation. Fernández-López et al. (2009) observed that a silica shell causes a red shift in the LSPR peak, depending on silica layer thickness and gold nanostructure size [100]. Liu et al. (2021) [101], demonstrated that an Au@Ag@PEG/Apt prodrug showed improved conversion and an enhanced photothermal response. Combining gold nanoparticles with support materials significantly enhances therapeutic potential, offering new avenues for effective cancer treatment [101].

3.4. Carbon-Based Nanomaterials (CNTs, Graphene)

Porous materials like carbon nanotubes (CNTs), graphene, and carbon dots (C-dots) are effective substrates for Au/Ag nanoparticles, enhancing therapeutic properties. These materials are widely used as photothermal therapy (PTT) agents due to their broad absorption spectrum and photothermal conversion capacity. Functionalization with biomolecules enhances biocompatibility and tumor-targeting specificity, minimizing adverse effects on healthy cells. Shape, size, porosity, and geometry are critical to their effectiveness.

Graphene efficiently converts energy into heat due to its large surface area and photothermal effect. Various graphene nanostructures have been designed for PTT. Graphene oxide, in particular, enhances NIR absorption and photothermal potential when combined with gold nanoparticles [102].

Gold nanorods modified with graphene oxide (GO) and functionalized with hyaluronic acid demonstrate increased NIR absorption and photothermal effect, enhancing cancer cell elimination. Gold-graphene nanohybrids show promise in PTT for glioblastoma and breast cancer, reducing tumor size and inducing necrosis [103].

Similarly, Qiu et al. (2020) used GE11 peptide-modified GO nanosheets loaded with 5-FU for combined PTT/chemotherapy in colorectal cancer [104]. The nanomaterial demonstrated antitumor effects in mouse models under 808 nm NIR laser irradiation, highlighting the potential of carbon nanostructures for cancer treatment. Future studies should carefully monitor adverse effects.

3.5. Other Inorganic and Hybrid Nanomaterials

Combining nanoparticles with magnetic and plasmonic properties on a single platform offers significant potential for biotechnology applications such as hyperthermia, regenerative medicine, and bioimaging as shown in Figure 8. For example, magnetite particles coupled with the optical properties of gold nanoparticles and their high biomolecular affinity make these hybrids excellent candidates for biomedical applications.

Beyond the systems illustrated in Figure 8, Zhang et al. (2018) [91] synthesized Au@Ag core–shell nanoparticles (~40–60 nm) modified with antibodies (Ab) and prostate-specific antigen (PSA), forming PSA-Ab-Au@Ag immunocomplexes. This nanoplatform served as a chemiluminescence (CL) biosensor for PSA detection. Au@Ag nanoparticles exhibited synergistic catalytic activity and effective sensitization in the luminol-K₃Fe(CN)₆ CL system, achieving recoveries between 86.1% and 112.5% in human serum samples, demonstrating selectivity and reliability for PSA detection [91]. No evaluation of biodistribution or long-term toxicity was reported, which represents a limitation for clinical translation.

The catalytic properties of Au@Ag nanoparticles highlight their potential in biochemical analysis and clinical diagnostics, particularly for the sensitive detection of tumor biomarkers such as PSA. These tools offer effective alternatives for analyzing biomarkers in complex samples.

Kulpa-Greszta et al. (2023) developed Fe₃O₄@SiO₂@Au heterostructures (~50–80 nm) using a three-step process, forming nanoparticles with a cubic Fe₃O₄ core, an amorphous silica layer, and gold nanoparticle islands [54]. These heterostructures exhibited strong responses to alternating magnetic fields (AMF) and NIR laser light, achieving temperature increases of 41–56 °C through combined AMF (330 kHz, 27 kA/m) and NIR laser (900 mW) applications. This dual-response capacity inhibited cell growth in breast cancer lines, demonstrating potential for hyperthermia applications. Although the therapeutic potential was demonstrated, the authors did not discuss biodistribution or possible accumulation of Fe and Au in vivo.

Nanocomposites have shown remarkable potential in photothermal therapy (PTT). For example, Zhang et al. (2024) synthesized Au@Ag@MB@SiO₂@Au core–shell-satellite nanocomposites (CSSNs ~80–100 nm) incorporating methylene blue (MB) [106]. CSSNs combined photothermal, redox catalytic, and photosensitizing properties, achieving 25.17% photothermal conversion efficiency under NIR irradiation and excellent photostability across cycles. In vivo tumor xenograft studies confirmed their efficacy in tumor suppression with no systemic toxicity. RGD-modified CSSNs (RCSSNs) enhanced tumor targeting, producing maximum intracellular ROS under dual-laser irradiation (660 nm and 808 nm), effectively eliminating 4T1 breast cancer cells and minimizing systemic damage. This suggests improved safety, though longer-term biodistribution studies remain necessary.

Histological analysis indicated biocompatibility of CSSNs, supporting their multifunctionality for combined cancer therapies.

Black phosphorus, copper sulfide, and copper selenide are promising alternatives to gold nanoparticles for PTT due to their superior photoelectric performance, high NIR molar absorption coefficients, and enhanced photothermal conversion efficiency (PCE). For instance, iron oxide nanomaterials (e.g., maghemite, magnetite) also exhibit plasmonic properties suitable for PTT, albeit requiring higher energy to excite free electrons compared to gold. Synthesis of gold-iron oxide hybrids offers enhanced PTT capabilities and responsiveness to magnetic fields, increasing tumor-targeting efficiency [45].

Bai et al. (2015) [107] developed hollow gold nanospheres (~30–40 nm) functionalized with dimercaptosuccinic acid and folic acid for cervical cancer imaging and PTT. These nanohybrids achieved a temperature increase of 63.4 °C in tumor regions under NIR irradiation [107]. Similarly, Liang et al. (2015) reported PEGylated gold-iron oxide nanohybrids inducing temperature increases of up to 52 °C in breast tumors following NIR exposure, enhancing survival rates in mice [108]. Both studies confirmed therapeutic efficacy, but information on nanoparticle clearance and excretion was limited.

Manganese oxide (MnO₂) nanoparticles are emerging as theranostic agents due to their strong magnetic resonance properties and responsiveness to tumor microenvironment conditions, such as pH and H₂O₂ levels. Reported MnO₂ nanoparticles typically ranged from 20 to 80 nm. Studies have shown MnO₂ nanoparticles, combined with polydopamine (PDA) or other agents, to enhance PTT efficiency by addressing limitations in antitumor activity at low concentrations [109,110,111,112].

Shin et al. (2019) [113] developed multifunctional conjugates based on hyaluronic acid-modified molybdenum disulfide (HA-MoS₂) for multimodal bioimaging and PTT in nude mice bearing CRC HCT116 tumors. These MoS₂ nanoparticles, conjugated with thiolated hyaluronic acid (HA), exhibited enhanced physiological stability, biocompatibility, and tumor-targeting efficiency. HA facilitated the targeted delivery of MoS₂ to tumor cells via interaction with the HA receptor. Once internalized by cancer cells, the HA-MoS₂ bond was disrupted, enabling the nanoparticles to accumulate in the cytoplasm. This accumulation enhanced the optical signal and the photothermal effect, demonstrating the potential of the HA-MoS₂ nanoplatform for tumor-targeted imaging and therapy under both pulsed and continuous NIR radiation [113].

Sun et al. 2019 prepared PDA@ut-MnO₂/MB nanoflowers, demonstrating high photothermal conversion efficiency and synergistic PTT and PDT effects [114]. In vivo studies with colorectal tumor models confirmed almost complete tumor suppression guided by magnetic resonance imaging. Similar success was reported by Zhao et al. (2017) using PVP-modified MoS₂ nanosheets [115].

Li et al. (2022) [116] developed MnO₂@mPDA-PEG nanoparticles, where PEG enhanced biostability and promoted accumulation in colorectal tumors. Mn²⁺ ions in the platform served as MRI contrast agents and boosted the immune response, demonstrating potential as theranostic agents to enhance systemic anti-tumor immunity. These findings highlight the therapeutic promise of MnO₂-based nanomaterials and encourage further research into MnO₂ nanoplatforms for photothermal therapy (PTT) in cancer treatment [116].

Li et al. (2023) [105] evaluated Au@MnO₂ nanoparticles (~60–90 nm) as photothermal agents. Under NIR laser irradiation, these nanoparticles increased temperatures by approximately ΔT = 18 °C, significantly outperforming MnO₂ nanoparticles (ΔT = 8 °C) and gold nanoparticles (ΔT = 5 °C) alone. However, photothermal efficiency was somewhat reduced by ascorbic acid’s corrosive effect on the MnO₂ layer, which diminished the temperature rise. These results underscore the potential of Au@MnO₂ nanoparticles for photothermal detection and quantitative analysis of alkaline phosphatase (ALP) activity [105]. The study focused on efficacy, but did not evaluate biodistribution or off-target effects.

In another study, Slama et al. (2024) explored Fe₃O₄@Au nanoparticles (~40 nm) as radiosensitizers for human lung cancer (A549) radiotherapy [117]. Synthesized using green chemistry and sonochemical methods, these nanoparticles showed significant internalization and accumulation in A549 cells within 24 h. Nanoparticles generated reactive oxygen species (ROS), triggering apoptosis and necrosis in tumor cells. Combined with irradiation, Fe₃O₄@Au nanoparticles amplified the pro-inflammatory response by upregulating cytokines like TNF-α, IL-1β, and IL-6. At higher concentrations and longer exposures, the nanomaterial induced apoptosis and secondary necrosis while inhibiting cell growth, demonstrating its radiosensitizing potential. The gold coating reduced aggregation, enhancing ROS production, oxidative stress, and inflammation, further potentiating ionizing radiation effects. While cytotoxicity in tumor cells was well characterized, effects on healthy tissues or systemic accumulation were not assessed.

Incorporating other metals into gold nanomaterials can improve photothermal efficiency. For example, Leng et al. (2018) [118] coated gold nanorods with copper sulfide, resulting in a red shift in the localized surface plasmon resonance (LSPR) peak and enhanced light-to-heat conversion. These gold-copper nanohybrids exhibited high photothermal stability, achieving temperature increases of up to 60 °C after four irradiation cycles [118]. Similarly, Maji et al. (2018) [119] coated gold bipyramids with molybdenum disulfide, leading to a red shift in the LSPR peak and enhanced photothermal performance. These hybrids increased temperatures above 60.3 °C and reduced HeLa cell viability following NIR laser irradiation [119].

4. Functional Modifications and Dye Encapsulation

Encapsulation of NIR-sensitive small molecules has also shown promise. Dyes such as indocyanine green (ICG) and heptamethine cyanines (e.g., IR780) enhance gold nanostructures’ optical and photothermal properties.

4.1. Incorporation of NIR-Sensitive Dyes (e.g., ICG, IR780)

ICG, a clinically approved dye, absorbs strongly at 780 nm, converting light into heat and generating ROS under NIR irradiation. Studies report that gold nanoclusters loaded with ICG achieved temperatures up to 70 °C, effectively reducing breast tumors in animal models. Similarly, gold nanostars stabilized with bovine serum albumin and loaded with ICG reached 63 °C, facilitating glioma cell ablation [38].

Despite these advantages, molecular dyes face challenges such as low photothermal conversion efficiency (PCE) and limited resistance to photobleaching. While IR780 outperforms ICG in certain aspects, its hydrophobicity, toxicity, and photodegradation limit its application. Encapsulation in gold nanostructures mitigates these drawbacks. For instance, gold nanospheres coated with Pluronic and loaded with IR780 showed significant temperature increases during NIR irradiation, demonstrating potential for colon carcinoma PTT [38]. Recent advances also explored ultrasmall-in-nano architectures functionalized with IRDye 800 CW NHS ester, designed to provide strong NIR responsiveness for diagnostic imaging while enabling therapeutic outcomes. For example, non-persistent plasmon nano-architectures (tNAs-IRDye) combined photoacoustic imaging with photothermal therapy, demonstrating significant tumor suppression in HPV-negative head and neck carcinoma murine models [120].

4.2. Polymer Coatings and Surface Functionalization

The efficiency of photothermal agents can be significantly improved by combining gold nanostructures with organic materials. Organic semiconductor polymers, such as polyaniline and polypyrrole, are designed to optimize solubility, stability, and drug-loading capacity. These polymers induce localized hyperthermia, reducing the need for high laser doses while offering excellent biocompatibility, high extinction coefficients, photostability, and tunable design. Additionally, their surfaces can be functionalized with targeting or imaging agents for tumor-specific delivery [121].

In PTT, these nanoparticles enhance therapeutic efficacy by improving the distribution of agents and the thermal response, making them promising theranostic tools. Recent studies have reported the preparation of PLGA nanoparticles modified with polydopamine and Mn²⁺ ions, loaded with doxorubicin, enabling the combination of thermal therapy with magnetic resonance imaging [122].

Mu et al. (2021) synthesized core–shell nanoparticles of gold, silver, and chitosan (Ag@Au-CS NPs) using a sol–gel reaction [123]. Chitosan stabilized the nanoparticles and provided superior antibacterial properties, which were demonstrated through bacterial growth inhibition assays against Escherichia coli. Ag@Au NPs exhibited cytotoxic effects against breast (MCF7) and cervical (HeLa) cancer cells, with decreased cell viability proportional to nanoparticle concentration, underscoring their potential in antimicrobial and oncological applications. Furthermore, Ag@Au core–shell nanoparticles coated with polyethylene glycol (PEG) (PSAuNPs) and functionalized with the GMT8 aptamer (GSAuNPs) demonstrated effective targeting of U87 glioma cells both in vitro and in vivo [124].

In vivo studies reveal that GSAuNPs showed enhanced tumor targeting and retention [124]. Mice treated with GSAuNPs combined with radiotherapy exhibited significantly prolonged survival. Cellular studies indicate that GSAuNPs penetrated the cytoplasm of U87 cells, while in normal human microvascular endothelial cells (HMEC-1), they remained mostly around the cell membrane. Importantly, elevated reactive oxygen species (ROS) levels were observed under irradiation, disrupting redox balance, causing DNA damage, and triggering apoptosis. The synergistic effect of nanoparticles and irradiation produced higher apoptosis rates than irradiation alone, demonstrating that GSAuNPs are effective nano-radiosensitizers for glioma-targeted therapy. As illustrated in Figure 9 [51], AuNPs can act as carriers of drugs and siRNA (which remain intact until delivered intracellularly) while also mediating ROS generation upon irradiation.

4.3. Optimization of Size, Shape, and Surface Charge

Hu et al. (2020) [125] developed a nanohybrid of polypyrrole (PPy) and PEGylated gold (~50–70 nm overall dimension) to enhance PTT for breast tumors. The addition of gold beads improved light-to-heat conversion efficiency from 35.3% to 37.1%, achieving a temperature of 55.6 °C under 808 nm NIR laser irradiation. Enhanced PTT efficacy against 4T1 cancer cells was observed, with cell viability decreasing to 25.2–34.9% after irradiation [125]. No data on biodistribution or excretion were provided, which limits assessment of systemic safety.

Puleio et al. (2020) [126] coated gold nanorods (AuNRs ~45 × 12 nm) with PHEA, incorporating lipoic acid (LA), PEG chains, folate, and irinotecan (Iri). The nanorods demonstrated effective tumor accumulation and reduced tumor growth under laser irradiation. In vivo studies with colon cancer xenograft models showed complete tumor eradication. The nanorods exhibited excellent aqueous stability and efficacy, highlighting their potential for combined PTT and chemotherapy in colon cancer [126]. Although the therapeutic efficacy was remarkable, the study did not report long-term accumulation or clearance of AuNRs, which is crucial for safety evaluation.

Duan et al. (2022) [42] synthesized dumbbell-shaped Au-Pt bimetallic nanorods (AuPtNRs ~60 × 15 nm) by depositing platinum (Pt) at the ends of AuNRs, followed by polydopamine (PDA) functionalization, yielding AuPt@PDA nanoparticles (~70–80 nm). These nanohybrids achieved superior photothermal conversion efficiency (81.78%) compared to AuNRs (52.32%) and AuPtNRs (78.76%). The Pt layer and PDA coating enhanced thermal stability and cellular dispersion [42].

AuPt@PDA nanoparticles reduced human melanoma (A375) cell viability from 91.12% to 39.36% after PTT laser exposure, with small size facilitating cytoplasmic uptake. ROS levels induced by thermal stress were significantly lower, minimizing oxidative damage and toxic effects on healthy tissues. The PDA coating also reduced cytotoxicity, making AuPt@PDA an ideal candidate for PTT, improving therapeutic efficacy while minimizing side effects. Despite these encouraging results, the absence of biodistribution and in vivo accumulation data limits translational assessment.

5. Biomedical Applications

Biomedical optics plays a pivotal role in tumor diagnosis and optical therapy. The wide range of applications in this field, from photon-based diagnostics to tumor ablation through optical therapies. Phototherapy, encompassing photothermal therapy (PTT) and photodynamic therapy (PDT), have shown exceptional targeting and selectivity in cancer treatment. However, traditional PTT/PDT approaches are often limited by their inability to specifically recognize disease sites [45].

5.1. Photothermal Therapy (PTT) in Cancer Treatment

PTT is a non-invasive treatment strategy that employs lasers to activate photothermal agents. Unlike PDT, PTT does not require oxygen to interact with target tissues. Instead, it converts photon energy into heat, inducing localized hyperthermia that kills cancer cells. This approach utilizes light-absorbing agents, such as metal nanoparticles, which generate heat under near-infrared (NIR) laser irradiation, effectively ablating tumors. The efficiency of thermal ablation depends on the photothermal agent’s ability to convert light into heat. PTT offers advantages such as reduced side effects and lower risk of drug resistance. The optical properties of plasmonic photothermal agents (PTAs) are determined by nanoparticle size and shape.

Since the 1990s, various PTT drugs have been developed, with gold nanoparticles (AuNPs) being the most extensively studied. The first clinical trial using AuNPs (AuroShell) in PTT began in 2009, demonstrating efficacy and safety in treating head and neck cancers, later extending to lung cancer. Subsequent studies confirmed similar outcomes for prostate cancer, reporting only mild side effects. However, challenges such as long-term toxicity and limited penetration into deep tissues have hindered clinical progress [127]. Despite these obstacles, phase I and II clinical trials using gold nanoparticles and agents like indocyanine green (ICG) have shown promising results in treating cancers such as metastatic breast and prostate cancers.

5.2. Photodynamic Therapy (PDT): Mechanisms and Limitations

PDT is a localized cancer treatment utilizing photosensitizing agents that absorb light at wavelengths below 600 nm [128,129]. Figure 10 provides a visual representation of this process, showing the generation of singlet oxygen and ROS that trigger apoptosis, necrosis, or autophagy in cancer cells [130]. PDT has demonstrated efficacy in treating cancers such as bladder, esophageal, skin, and brain cancers, as well as early-stage and obstructive lung cancers [129,131].

The effectiveness of PDT depends on factors like photosensitizer properties, tumor site accumulation, and metabolism. Selective tumor accumulation relies on the chemical properties of the photosensitizer and the vascular permeability of tumors, which facilitates retention. Carrier proteins can further enhance selective targeting. Beyond inducing direct tumor cell death, PDT stimulates immune and inflammatory responses, amplifying therapeutic effects. This cytotoxic response recruits macrophages to phagocytize damaged tumor cells and neutrophils to aid in tumor destruction [101,130].

Over the past four decades, PDT has been used clinically to treat precancerous and non-melanoma skin cancers. Clinical trials are exploring its application in other cancers, driving the development of improved photosensitizers.

First-generation photosensitizers are water-soluble, allowing for intravenous administration, and exhibit low toxicity alongside antitumor effects. However, their limited tissue penetration restricts clinical use [132]. Photofrin^®, the most successful first-generation photosensitizer, is approved for treating bladder, esophageal, and lung cancers, but is limited by its short excitation wavelength and cutaneous toxicity [133].

Second-generation photosensitizers, such as porphyrin derivatives and non-porphyrin compounds, offer higher molar absorption coefficients, improved singlet oxygen generation, and longer excitation wavelengths, enabling deeper tissue penetration. Despite these advancements, challenges like low water solubility and lack of tumor specificity persist, leading to systemic distribution post-administration. Examples include 5-ALA, temoporfin, and verteporfin, which show enhanced performance in treating residual gliomas post-surgical resection [134,135].

Third-generation photosensitizers aim to enhance tumor targeting and tissue penetration through protein or peptide conjugation and nanoparticle encapsulation. Donor-acceptor (DA) molecules are also being explored for their long emission wavelengths [136].

Despite promising results, PDT’s dependency on oxygen in tumor tissues and its impact on the immune system remain challenges. Research continues to focus on developing next-generation photosensitizers with improved tissue permeability, photobleaching resistance, and enhanced therapeutic performance.

5.3. Combined Therapies: PTT with Chemotherapy, Immunotherapy

Integrating multimodal therapies into a single nanoplatform offers a promising strategy to overcome the limitations of conventional monomodal therapies. Combining PTT, chemotherapy, gene regulation, and immunotherapy can produce synergistic effects, reducing toxicity while enhancing efficacy and safety. This approach safeguards healthy tissues and enables precise monitoring of treatment progress.

Nanoparticle-mediated PTT has been investigated both as a standalone treatment and in combination with other therapies. Figure 11 illustrates this combined therapeutic strategy, in which photothermal agents are loaded with chemotherapeutic drugs like DOX or curcumin, achieving improved treatment outcomes over monotherapies. For example, Wang et al. (2020) [137] developed a nanomaterial comprising silver-coated gold nanorods (Au@Ag) loaded with paclitaxel (TAX) in liquid lipid vesicles (LV). This nanomaterial remains inactive under normal physiological conditions, becoming active in the hydrogen peroxide (H₂O₂)-rich tumor environment. Activation occurs as the silver coating is removed, exposing the gold nanorods for PTT while releasing TAX for chemotherapy [137]. Similarly, Mapanao et al. (2021) reported non-persistent ultrasmall-in-nano gold architectures incorporating an NIR-absorbing gold core and a cisplatin prodrug, which achieved synergistic chemo-photothermal efficacy in three-dimensional head and neck squamous cell carcinoma models, particularly in HPV-positive tumors [138].

Hyaluronic acid (HA)-coated nanocomposites encapsulating DOX offer another example. HA serves as a biodegradable targeting and encapsulation agent [139]. Additionally, thermosensitive hydrogel-coated nanospheres release drugs in response to temperature increases induced by near-infrared (NIR) irradiation [140]. Folic acid coatings further enhance tumor-specific targeting.

Immunotherapy, which activates the immune system to destroy cancer cells, achieves enhanced outcomes when combined with PTT. During PTT-induced cancer cell death, heat shock proteins and antigens are released, stimulating immune responses. Animal models have shown that combining PTT with adoptive T-cell transfer (ATCT) reduces tumor recurrence [138,141]. Combining PTT with immunotherapy using photo-absorbing agents holds promise for preventing recurrence and targeting metastases.

5.4. Theranostics: Integration of Diagnosis and Therapy

Similarly, integrating PTT with chemotherapy via gold nanoparticles (AuNPs) enhances tumor ablation and inhibits metastasis more effectively than monotherapies.

Li et al. (2020) [142] developed a bimetallic nanoenzyme (AgPd@BSA/DOX ~50–70 nm) with peroxidase-like activity for DOX delivery. This nanostructure combines photothermal conversion with catalytic production of hydroxyl radicals (HO•), significantly enhancing antitumor effects. The core–shell nanoparticles demonstrated superior photothermal efficiency and catalytic activity compared to pure silver nanoparticles [142].

In vitro and in vivo studies confirmed efficient HO• radical production and hyperthermia induction under NIR irradiation, facilitating DOX release for triple-combination therapy. The bovine serum albumin (BSA) layer improved biocompatibility and DOX adsorption. Under 808 nm laser irradiation, tumor temperatures rose to 44 °C, effectively eliminating cancer cells. Drug release efficiency reached 85.6% at pH 5.5 and 40.8% at pH 7.4. Hemolysis assays confirmed low toxicity and high biocompatibility. HeLa cell studies revealed increased DOX uptake with laser irradiation, resulting in high cell mortality. In treated mice, tumor temperatures rapidly increased to 50 °C under laser irradiation. However, long-term biodistribution and excretion data were not reported, limiting the assessment of systemic safety. These results highlight the potential of AgPd@BSA/DOX as an innovative drug delivery system integrating photothermal, chemotherapeutic, and catalytic mechanisms [142].

Rodrigues et al. (2019) [143] developed mesoporous silica nanorods with a gold core (Au-MSS) functionalized with TPGS and PEI via electrostatic or chemical bonding methods. While functionalization slightly reduced drug encapsulation efficiency, it preserved PTT capability [143].

In vitro assays confirmed biocompatibility at concentrations below 100–125 μg/mL, with toxicity observed above this threshold. FTIR analysis verified the complete removal of the CTAB surfactant, confirming the nanorods’ suitability for therapeutic use. The Au-MSS/TPGS-PEI and Au-MSS/TPGS/PEI (3:1) formulations generated sufficient temperature increases (~40 °C) for therapeutic effects and were effectively internalized by HeLa cells, enabling efficient intracellular drug release. Nonetheless, the study did not evaluate biodistribution or clearance, which represents a limitation for future translational applications.

These findings underscore the therapeutic potential of modified Au-MSS nanoparticles for combining PTT and drug delivery. The formulations offer enhanced selectivity and reduced side effects compared to conventional therapies, positioning them as promising candidates for cancer treatment.

6. Optical Detections and Tumor Theranostics

Optical detection combines traditional methods like colorimetry, luminescence, and spectral analysis to identify and quantify substances, enabling faster and more accurate cancer diagnostics. As shown in Figure 12, this dual diagnostic and therapeutic potential, termed theranostics, is exemplified by plasmonic nanoparticles.

6.1. Optical and Spectroscopic Diagnostic Techniques

Techniques such as fluorescence spectra, chemiluminescence, and Raman scattering allow for molecular and cellular-level analysis, while biomarkers are identified using immunoassays, molecular hybridization, PCR, and biochips for early tumor detection.

Imaging methods, including MRI, CT, ultrasound, nuclear medicine, and optical imaging, are widely employed for tumor diagnosis, treatment guidance, and prognosis evaluation [31,144]. Optical imaging uses near-infrared (NIR) light for deep tissue penetration and reduced phototoxic damage [44]. Theranostics integrates diagnostic and therapeutic functions into a single nanoparticle platform, combining imaging techniques like MRI and tomography with targeted treatments such as PTT [31,44]. Phototherapeutic agents, including metal, polymer, and carbon nanoparticles, enhance tumor treatment by generating fluorescence, heat, and reactive oxygen species (ROS), enabling precise imaging and controlled drug release [31,44,102,144].

6.2. Fluorescence-Guided Imaging and PTT (NIR-II)

Combining PTT and PDT facilitates real-time fluorescence imaging for tumor localization, improving diagnostic accuracy and therapeutic outcomes. However, challenges such as tissue autofluorescence and dispersion need to be addressed to optimize theranostics [45]. Fluorescence-guided NIR-II phototherapy offers a promising alternative for cancer treatment, although the low efficiency of PDT with NIR-II fluorophores remains a limitation. Advances in molecular design have led to the development of novel NIR-II photosensitizers, such as carbon nanotubes (~1–2 nm diameter, hundreds of nm in length), conjugated polymers (10–50 nm aggregates), semiconductor quantum dots (typically 5–10 nm), and organic dyes (<2 nm), improving imaging resolution and tissue penetration [44,45,102]. Despite progress, limited clearance data and potential long-term accumulation remain concerns.

NIR-II fluorophores combine imaging and therapy by converting excitation energy into heat, enabling precise tumor targeting. The NIR-II laser (1064 nm) offers deeper tissue penetration and greater safety than NIR-I lasers. Agents such as IR-780 and IR-825 exhibit fluorescence and photothermal properties, with IR-825 demonstrating enhanced safety and efficacy in breast cancer models [44,45]. NIR-II fluorescence imaging provides higher signal-to-noise ratios and improved spatial resolution, minimizing interference from biomolecule dispersion and autofluorescence. However, IR-780 toxicity at high doses underscores the need for further toxicological evaluations in healthy models [45,144,145].

Recent advancements include single-walled carbon nanotubes (SWCNTs ~1–2 nm diameter) and InGaSn-based fluorescent probes (~5–10 nm), achieving tissue penetration depths of up to 3 cm. However, challenges like low fluorescence yield and limited biocompatibility persist. Innovations such as BBTD-based fluorophores, particularly CH1055-PEG (hydrodynamic diameter ~3–5 nm), have shown superior in vivo imaging performance for vascular systems and deep tumors [44,45,146,147].

Small molecular fluorophores with low band gaps also enable heat conversion, making NIR-II fluorescence imaging integrated with PTT a promising cancer treatment strategy [45]. These fluorophores act as agents for image-guided PTT, facilitating precise tumor diagnosis and treatment.

PTT agents with imaging capabilities, such as IR-780 and IR-825, have been applied in fluorescence-guided tumor PTT. IR-780 demonstrates both fluorescence and photothermal conversion properties, but its toxicity at high doses limits its application. In contrast, IR-825 addresses this limitation, enabling effective thermal ablation in breast cancer models [148,149]. Still, systematic biodistribution and excretion studies of these cyanine derivatives remain scarce.

NIR-II fluorescence imaging at wavelengths up to 1320 nm achieves a signal-to-noise ratio 100 times higher than imaging at 850 nm. This improvement, combined with reduced biomolecule dispersion and autofluorescence, enhances spatial resolution and tissue penetration [45,146]. For example, SWCNTs and InGaSn-based materials developed by Hong et al. (2012) [147] achieve spatial resolutions of ~25 μm and penetration depths of up to 3 cm. Despite these advancements, low fluorescence yield, poor biocompatibility, and limited water solubility remain significant obstacles for NIR-II probes [147].

In 2014, Hong et al. synthesized pDA, a polymer emitting fluorescence above 1000 nm. Subsequently, BBTD was developed to capture in vivo NIR-II fluorescence images, demonstrating high fluorescence efficiency within the NIR-II window. Derivatives such as M1 and CH1055, based on BBTD, also exhibited emissions above 1000 nm. Notably, CH1055-PEG enabled imaging of the cerebral vascular system and deep tumors in mice [150].

The synthesis of new fluorophores with enhanced tissue penetration and sharper imaging remains a key focus in fluorescence imaging. Developing fluorophores with superior optical properties and biocompatibility continues to be a critical challenge in the field. Importantly, while several NIR-II dyes demonstrate good short-term tolerance, their pharmacokinetics, clearance routes, and long-term toxicity are not fully established [45,150,151].

Small-molecule organic dyes are promising candidates for NIR-II fluorescent probes due to their excellent biocompatibility and favorable pharmacokinetics, making them suitable for clinical applications. Fluorescent molecules like cyanines, BODIPYs, and BBTDs have been optimized for the NIR-II region. For example, ICG (~1 nm), a cyanine dye, is widely used for real-time vascular imaging, surgical guidance, and tumor monitoring. Although its primary emission peak lies in the NIR-I range, it extends into the NIR-II window [45].

New NIR-II fluorophores derived from cyanine dyes, including IR26, Flav7, FD-1080, CX-3, and BTC-1070 (all <2 nm), exhibit improved fluorescence in the NIR-II spectrum. Similarly, BODIPY- and squaraine-based fluorophores have been advanced through structural modifications such as nitrogen incorporation.

Most clinical photosensitizers emit fluorescence below 800 nm, limiting their use in photodynamic therapy (PDT) within the NIR-II window. Strategies like donor-acceptor structures and steric hindrance have been explored to overcome this limitation. Photosensitizers such as DPP-BT, COi6-4Cl, and BNET promote singlet oxygen (¹O₂) formation. Additionally, type I photosensitizers, like TQ-TPA and TSSAM, produce cytotoxic free radicals via electron/proton transfer, enabling NIR-II fluorescence imaging and PDT guidance. While primarily classified as NIR-I photosensitizers, these compounds can also function in the NIR-II window [151,152].

Single-walled carbon nanotubes (SWCNTs ~1–2 nm) exhibit strong fluorescence, while gold nanoparticles (AuNPs 20–50 nm) serve as contrast agents in imaging techniques like CT, MRI, SPECT, PET, and photoacoustic imaging, aiding therapy monitoring [144]. Incorporating elements such as gadolinium (Gd) enables dual-mode imaging (CT and MRI), while radioisotope labeling (e.g., ⁶⁴Cu) facilitates nuclear imaging (PET/SPECT) [145,146].

6.3. Nanoplatforms for Dual Imaging and Treatment

Despite advancements, NIR-II fluorophores require further development to achieve greater stability, precision, and extended absorption/emission wavelengths. The integration of NIR-II fluorescence imaging with PTT or PDT holds promise for targeting cancer cells while minimizing damage to healthy tissue [153].

Mesoporous silica shell nanorods with gold cores (AuMSS ~80–120 nm) exemplify multifunctional materials for bioimaging and therapy. As noted by Rodrigues et al. (2019) [154], gold nanorods are effective photothermal agents and drug carriers. However, therapeutic efficacy declines due to protein corona formation in the bloodstream, necessitating strategies to extend circulation half-life [154].

Combining chemotherapy with PTT using AuMSS has proven effective in eradicating HeLa cells. Rodrigues et al. (2024) [153] developed AuMSS-based materials functionalized with polyethylene imine (PEI) and red blood cell-derived membranes (RBC), loaded with acridine orange (AO). The seed-mediated synthesis yielded rod-shaped structures with gold cores and uniform mesoporous silica shells (~90–110 nm) [153].

RBC-derived membranes neutralized the AuMSS surface charge, enhancing colloidal stability and biocompatibility. Functionalized AuMSS nanorods demonstrated improved cellular internalization and reduced hemolysis, achieving a surface charge near ±2 mV for optimal circulation and extended half-life. Importantly, functionalization preserved photothermal and drug-loading properties, achieving conversion efficiencies of 72–75% and high biocompatibility in HeLa and FibH cells. However, no long-term biodistribution or excretion data were reported, which limits safety assessment.

The anticancer potential of chemo-PTT using AuMSS/PEI/RBC_AO nanorods was evaluated in HeLa cells. Combined therapies reduced cell viability, with dose-dependent effects observed at concentrations above 200 μg/mL. Chemo-PTT reduced viability by 59% at 100 μg/mL and 95% at 200 μg/mL, highlighting the potential of AuMSS nanomaterials in cancer treatment. Functionalization with PEI and RBC enhances biological performance, contributing to therapeutic efficacy [153].

Gold nanorods (~40 × 10 nm) offer high absorption–dispersion ratios and tunable localized surface plasmon resonance (LSPR) effects. However, heating-induced structural changes can reduce photothermal conversion efficiency (PCE). Platinum nanoparticles (PtNPs ~3–5 nm), known for their photothermal stability and catalytic properties, can be grown on gold nanorods (AuNRs) to enhance nanostructural stability and modulate LSPR.

Polydopamine (PDA), a biocompatible polymer with excellent energy absorption and photothermal conversion properties, reduces reactive oxygen species (ROS)-induced toxicity, offering significant potential in biomedical applications [154].

Manivannan et al. (2019) [41] synthesized core–shell Ag@SiO@Ag nanostructures (~50–70 nm) using the Stöber method for bioimaging and PTT. Ag@SiO@Ag seeds exhibited superior photothermal efficiency and fluorescence emission compared to Ag@SiO@Ag nanoparticles, a difference attributed to the more uniform and continuous silver layer in the seeds, which enhances plasmonic coupling and light-to-heat conversion. The seeds induced significant tumor cell cytotoxicity at 41.5 °C and effectively destroyed tumor tissue above 43 °C under visible light exposure [41]. Ag@SiO@Ag seeds achieved temperatures up to 43 °C and demonstrated effective internalization in HeLa cells, supporting their potential as bioimaging probes and PTT agents. Biocompatibility assays indicated low toxicity, with cell viability at 90% for Ag@SiO@Ag nanoparticles and 70% for seeds under light exposure. However, in vivo biodistribution and systemic toxicity were not assessed [41].

He et al. (2021) [155] prepared hollow Ag-Au nanoshells coated with bovine serum albumin (BSA ~80 nm) to minimize cytotoxicity for PTT-based colon cancer treatment. These nanoshells generated strong LSPR and stable PTT effects under NIR irradiation, enabling image-guided therapy [155]. Although BSA coating improved compatibility, studies on long-term circulation and clearance are still lacking.

Beyond the intrinsic optical and functional properties of plasmonic nanomaterials, the design and evaluation of these structures for specific applications in phototherapy and diagnostics rely on advanced optimization methods. Three-dimensional modeling and computational simulations play a crucial role in predicting properties and guiding the development of nanomaterials with tailored characteristics [156,157]. Such approaches enable an in-depth analysis of the effects of structural variations, composition, and functionalization, contributing to the efficient selection of nanomaterials with superior performance.

7. Computational Tools for Nanomaterials Desing

Computational tools have become an important part of the design and evaluation of photoactive nanomaterials, especially for biomedical applications, by combining many domains of physics (e.g., optics, fluids) with numerical methods solutions, such as the Finite Element Method (FEM). Multiphysics simulation environments, for example, COMSOL Multiphysics, makes it possible to set up an entire simulation from the beginning by making a selection of the domain of physics, modeling the geometry of the system and setting parameters such as variables, boundary conditions and equations involved. The opportunity to simulate actual systems renders these methods powerful tools, with the possibility of predicting and tuning of material properties prior to synthesis, thus reducing costs and time associated with initial bench-scale experiments [158]. These methods are particularly valuable in the case of plasmonic nanomaterials, whose performance can be highly sensitive to subtle structural variations [159].

7.1. Numerical Simulations (FEM, FDTD)

One of the most important features of plasmonic nanomaterials is the LSPR effect, which governs their light-matter interactions. To study and optimize this phenomenon, numerical techniques such as the finite element method (FEM) and finite-difference time-domain (FDTD) simulations are commonly employed [160]. Numerical simulations are used to compute parameters like light absorption, scattering, and heat conversion efficiency, especially in the near-infrared (NIR) range (700–1100 nm), which is optimal for photothermal and photodynamic therapies. Simulations can reveal how factors such as the aspect ratio of gold nanorods or the shell thickness of core@shell structures affect photothermal conversion, guiding the design of nanostructures with enhanced therapeutic potential [161].

7.2. Light–Matter Interaction Modeling

Creating accurate 3D models of nanoparticles can be an essential step in these studies since detailed representations of the nanomaterial structures enable thorough computational analysis and optimization to guide the development of nanomaterials for biomedical applications [162]. Software like SolidWorks and AutoCAD are widely used to design geometries that range from simple spheres to more complex shapes such as nanostars, nanocages, and bipyramids [163]. These models are then implemented in multiphysics simulation platforms, such as COMSOL Multiphysics and others, which incorporate optical, thermal, and biological parameters to simulate realistic therapeutic environments. Such tools can predict how nanoparticles behave in tumor tissues, considering factors like optical properties of the medium, laser intensity, and heat dissipation [164].

7.3. Experimental Validation and Multiphysics Integration

Mathematical simulations can help to refine nanomaterial configurations and assess their therapeutic viability before moving on to experimental validation.

Computational simulations are also used to optimize nanomaterial-based therapies, since, in PTT, simulations assist in determining the best laser parameters, such as wavelength, power density, and irradiation time, to maximize tumor destruction while minimizing harm to healthy tissues [162]. Similarly, in PDT, simulations model the production and spread of reactive oxygen species (ROS), offering insights into how the therapy affects tissues [165]. An example is the use of FEM to simulate heat generation and distribution by gold nanorods embedded in a tumor tissue model. These studies emphasize the importance of nanoparticle concentration and distribution in achieving effective hyperthermia [166]. By combining simulation results with experimental data, it is possible to create better therapeutic protocols for clinical use.

7.4. AI and Multiscale Modeling for Predictive Desing

As computational power continues to grow and algorithms advance, 3D modeling and simulations will play an even greater role in nanomedicine. Computational tools not only enhance the design and optimization of nanomaterials, but also provide valuable insights into their interactions with biological systems, supporting the development of more effective and personalized therapies [167].

Many works have focused on the simulation of nanomaterials for PTT, changing parameters like morphology, size and type of nanoparticle, as well as the wavelength of incident light. Terrés-Haro and collaborators (2023) have investigated gold nanorods and gold nanostars, assessing the interaction between incident light and the nanoparticles, and its potential for heat production, as shown in Figure 13 [168]. Furthermore, by varying the morphology of the NPs, for example, the aspect ratio of the nanorods and the tip length of the nanostars, different results were obtained for the scattering and absorption cross-section, underscoring the interaction of the light with specific parts of the NPs. The heat produced after the interaction with light has shown a good correlation between simulation and experimental results.

Despite their advantages, computational methods still face challenges. High computational costs and the need for specialized knowledge can make these techniques less accessible. Also, the complexity of biological systems often requires simplifying assumptions, which may not fully represent in vivo conditions. In spite of these challenges, these tools can still provide significant insights on the research of photoactive nanomaterials, elucidating its functional mechanisms and revealing the applicability of new types of nanomaterials in photothermal therapy. Future improvements in this field are likely to involve integrating machine learning with traditional simulation methods. Modern approaches can help identify patterns in large datasets and speed up the optimization of nanomaterial properties [169,170]. Furthermore, developing multiscale modeling frameworks that link atomic, molecular, and macroscopic scales will improve the accuracy and scope of simulations [171].

Artificial intelligence is expected to reinforce this evolution by anticipating critical elements such as nanoparticle toxicity, biodistribution, accumulation, and therapeutic efficacy. These predictive models can significantly accelerate experimental design and reduce trial-and-error processes. While AI-based approaches are increasingly reliable thanks to advances in algorithms and data availability, their effectiveness ultimately depends on validation with high-quality and standardized biological data. Therefore, AI represents a complementary and promising tool to enhance the safety, selectivity, and translational potential of nanomedicine [163,167,169,170].

8. Comparative Analysis of Photoactive Nanomaterials

8.1. Key Optical Properties and Action Mechanisms

Understanding the unique properties and applications of photoactive nanomaterials is vital for optimizing their biomedical use, particularly in PTT and PDT.

Table 1. Comparative analysis of photoactive nanomaterials in biomedical applications.

Nanomaterial	Optical Properties	Mechanism of Action	Advantages	Limitations	Potential Clinical Applications	References
Gold (Au)	NIR absorption; tunable SPR	SPR-mediated heat generation; drug delivery	High biocompatibility; effective in imaging and PTT; simple and reproducible synthesis	High cost; cytotoxicity at high concentrations; risk of persistence and accumulation in the body	PTT, PDT, imaging diagnostic	[68,69]
Silver (Ag)	SPR in visible range; high conductivity	ROS generation; thermal conversion	Antibacterial properties; ease of synthesis	Cytotoxicity; reduced stability in biological environments	Combined PTT and PDT; antibacterial applications	[46,47]
Porous Silicon	Thermal stability; tunable porosity	Controlled drug release	High biocompatibility; integration with other materials	Altered optical properties upon functionalization	PTT, drug delivery systems	[38]
Iron Oxide (Fe3O4)	Magnetic and plasmonic properties	NIR-mediated heat conversion	Magnetic response; imaging properties	Requires high energy; potential cytotoxicity	PTT, magnetic hyperthermia; bioimaging	[54,107]
Manganese Oxide (MnO2)	High NIR absorption; paramagnetic	ROS generation; tumor microenvironment modulation	High photoconversion efficiency; low toxicity	Low efficacy at minimal concentrations	PTT, PDT, MRI diagnostic	[114,116]
Carbon Nanotubes (CNTs)	Broad NIR absorption; high conductivity	Thermal conversion for tumor ablation	Stability; functionalization for active targeting	Long-term toxicity concerns; synthesis challenges	Cancer therapy; drug delivery	[103,104]
MOFs	High porosity; therapeutic agent loading	Controlled drug release; plasmonic protection	Functional and tunable; combined therapies	Stability in biological environments	PTT, PDT, drug delivery	[11,98]

compares key nanomaterials, highlighting their optical characteristics, mechanisms of action, benefits, limitations, and clinical potential. Nanomaterials like gold (Au) and silver (Ag) nanoparticles dominate this field due to their high biocompatibility and tunable optical behavior.

8.2. Advantages and Drawbacks of Each Nanomaterial

Gold nanoparticles (AuNPs) are foundational in nanomedicine, excelling in both PTT and imaging diagnostics. Their tunable surface plasmon resonance (SPR) and stability make them ideal for tumor ablation, as demonstrated by Pakravan et al. (2021) [68] and Yang et al. (2021) [69]. However, high production costs and long-term cytotoxicity remain significant barriers to widespread clinical adoption. Silver nanoparticles (AgNPs) complement AuNPs with strong plasmon resonance in the visible spectrum and antibacterial properties. Their ability to generate reactive oxygen species (ROS) enhances combined PTT and PDT therapies, but potential cytotoxicity and reduced stability in physiological environments remain challenges [46,47].

8.3. Clinical Potential and Translational Readiness

Emerging nanomaterials, such as manganese oxide (MnO₂), porous silicon, and metal–organic frameworks (MOFs), expand the possibilities in nanomedicine. MnO₂-based nanostructures function as therapeutic and diagnostic agents, modulating the tumor microenvironment and serving as MRI contrast agents. However, their efficacy at minimal concentrations remains limited [114,116]. Porous silicon, with its biocompatibility and tunable porosity, offers potential for controlled drug release and enhanced photothermal applications [38]. Similarly, MOFs provide high porosity and protect plasmonic materials from degradation, with studies emphasizing their promise in PTT and PDT despite certain limitations [11,98,172,173,174].

Iron oxide nanoparticles (Fe₃O₄) are notable for their combined magnetic and plasmonic properties, making them suitable for hyperthermia and imaging. However, their lower light-to-heat conversion efficiency compared to gold-based systems suggests a need for hybrid materials to enhance performance [54,107]. Carbon nanotubes (CNTs) and gold nanostars also stand out for their high surface-area-to-volume ratios and exceptional photothermal efficiencies. CNTs offer stability and functionalization potential for targeted therapies, though concerns about toxicity and synthesis uniformity persist [103,104]. Gold nanostars demonstrate improved tumor penetration and immune response stimulation, showing promise for advanced cancer therapies [68,81].

9. Advances and Future Perspectives

While progress has been made in optimizing nanomaterials, challenges in toxicity, stability, and clinical translation remain. Future research should focus on hybrid structures that integrate material advantages, enabling multifunctional platforms with enhanced therapeutic and diagnostic capabilities.

9.1. Addressing Toxicity and Stability Challenges

Metallic nanoparticles in the 20–200 nm range offer significant biomedical potential; however, challenges related to toxicity and renal excretion remain unresolved [49]. Ensuring the effective delivery of gold nanoparticles (AuNPs) to tumors at therapeutic concentrations, alongside achieving sufficient near-infrared (NIR) light penetration through the blood–brain barrier, presents critical obstacles [38]. In this context, the ultrasmall-in-nano approach has emerged as a promising strategy to overcome the drawbacks of renal excretion and long-term accumulation, improving both clearance and safety profiles of AuNPs [82].

9.2. Optimization for Tumor Targeting, Excretion, and Selectivity

Addressing the excretion, degradation, and selectivity of plasmonic nanoparticles is paramount for safe and effective clinical applications. Particle size plays a pivotal role in toxicity and immune interactions: smaller nanoparticles (<10 nm) show enhanced renal excretion, but may lead to higher cytotoxicity due to biodegradation products, while larger particles (>10 nm) tend to accumulate in the liver and kidneys. Notably, smaller particles (~4 nm) may suppress inflammatory responses, whereas larger ones (14–100 nm) are more likely to provoke inflammation [50]. Poor control over particle size can also lead to degradation in the bloodstream rather than efficient excretion. For instance, smaller gold nanoparticles (~8 nm) have shown higher cytotoxicity compared to larger ones (~37 nm). Moreover, the chemical nature of the metal is also relevant: silver nanoparticles are prone to oxidation into Ag⁺ ions, which promotes degradation and interactions with proteins, particularly thiol-containing biomolecules [47,94].

Achieving tumor selectivity and avoiding damage to healthy tissues requires optimizing the physiological and pharmacokinetic stability of nanoparticles. The stability of conjugation with targeting agents, such as antibodies, must be carefully evaluated, as size, shape, charge, and surface chemistry strongly influence biological interactions. Biocompatibility can be improved by replacing toxic stabilizers like CTAB with safer alternatives such as PEG, chitosan, albumin, or silica. Despite promising preclinical outcomes, clinical translation faces challenges such as limited NIR penetration and suboptimal light-to-heat conversion efficiencies. These issues have spurred the development of nanocomposite platforms that combine PTT with imaging capabilities. Applying engineering principles to design nanoparticles with optimized photothermal properties improves efficacy, stability, and selectivity [155].

Advancing clinical applications also require improved pharmacokinetics to enhance tumor accumulation while reducing adverse effects. Strategies include developing ultrasmall plasmonic nanoparticles (<10 nm), such as gold and silver dots, to improve excretion and lower toxicity, as well as employing ultrasmall-in-nano architectures to overcome renal clearance limitations. Finally, identifying the most effective administration routes is vital to maximize therapeutic efficacy and minimize systemic side effects.

9.3. Ethical Considerations and Scalability

A significant gap persists between promising in vitro results and their successful translation to in vivo studies and clinical applications. Bridging this gap is crucial to validate the clinical potential of nanoparticles. Scaling up the synthesis processes for commercial production, while addressing environmental impacts, is another essential step. Ethical considerations, including the safe elimination of nanoparticles post-treatment and minimizing side effects, must also be addressed to ensure their responsible clinical use. Moreover, a major barrier to clinical translation is the lack of clearly defined and standardized regulatory requirements for nanomedicines. Current regulatory frameworks are often adapted from conventional drug approval processes and are not fully suited to address the unique physicochemical properties, biodistribution, and long-term safety concerns of nanoparticles. This regulatory gap complicates approval pathways, delays clinical validation, and ultimately hinders the widespread adoption of nanomedicine-based therapies [32,33,169,170,175,176].

10. Conclusions

This review examines recent advances in the design, synthesis, characterization, and photothermal performance of plasmonic and non-plasmonic photoactive nanomaterials, with particular emphasis on their structure–property relationships and biomedical applications. Plasmonic nanomaterials, such as Au and Ag nanoparticles, demonstrate exceptional photothermal conversion efficiencies due to their localized surface plasmon resonance (LSPR), which can be finely tuned through size, shape, and core@shell engineering. Similarly, non-plasmonic alternatives like CuS, TiN, MoS₂, and carbon-based nanostructures have shown promising photothermal properties, biocompatibility, and cost-effectiveness.

A comparative analysis of experimental results has highlighted the impact of composition, morphology, and surface chemistry on photothermal behavior and therapeutic potential. Moreover, simulation approaches based on finite element methods (FEM), particularly using COMSOL Multiphysics, have proven to be powerful tools for predicting optical and thermal responses at the nanoscale. These models allow for the evaluation of photothermal efficiency under realistic physiological conditions and provide valuable insights that guide experimental design.

Looking ahead, the rational design and optimization of photoactive nanomaterials using COMSOL and other computational tools is expected to play a critical role in advancing personalized nanomedicine, enabling precise control over heating profiles, improved therapeutic indices, and minimal off-target effects. Artificial intelligence will further accelerate this progress by predicting toxicity, biodistribution, accumulation, and therapeutic efficacy, reducing experimental trial-and-error and supporting safer and more selective clinical translation of nanomedicines. Integrating simulations with experimental validation will accelerate the development of next-generation nanomaterials tailored for safe and effective clinical applications in photothermal therapy and beyond.