Nanomaterials for combination cancer photothermal therapy

The biomedicine field has been significantly impacted by optical procedures using designed laser and optical equipment, and exploiting those are now evolving. In the field of cancer treatment through nanomedicine, advanced procedures including photothermal therapy (PTT) and photodynamic therapy (PDT) have been employed recently. However, using phototherapy methods alone is unable to entirely treat various cancers with different circumstances such as hypoxia, inaccessible location, side effect, and low tendency in some the immune system responses, which consequently leads to the risks of relapse and metastasis. Therefore, employing phototherapy in combination with other cancer treatments, such as chemotherapy, radiation, immune therapy, and gene therapy, can introduce a synergistic effect that can be achieved through nanomaterials. The purpose of this study is to describe the combinatorial strategies that show promise in tackling the obstacles of phototherapy and to bring attention to the role of light in the treatment of cancer.


Introduction
The use of particular light in certain wavelengths was used in light therapy and phototherapy to treat a variety of diseases. In the nineteenth century, light therapy as a pioneering technique was first used in modern medicine due to a clear understanding of the physical properties of light and its interactions with matter. This story commenced with using ultraviolet (UV) light for the purpose of lupus vulgaris treatment by physician Niels Finsen who was gifted the Nobel Prize in 1903. Treatment of hyperbilirubinemia in the 1960s through blue light was another promising accentuated for utilizing light therapy and phototherapy, which saved many babies [1]. In addition, utilizing laser in the different clinical areas including removing different spots on the skin [2,3], photodynamic therapy (PDT) [4,5], and photothermal therapy (PTT) [6,7] are only short list of the light therapy applications. Recent advances in nanomedicine have accelerated the development of light-induced theranostics based on adaptable nano agents. In this line, a variety of light-induced activities from near-infrared (NIR) to visible (Vis) lights offers a practical approach for clinically safe light irradiation tumor ablation [8,9]. In the various usage of light therapy biological windows region (650 to 1350 nm) has a comparatively high deep tissue penetration than in the visible region. The light in the biological windows region can stimulate nano agents for absorption and excitation and in some cases emission to generate photothermal conversion, photodynamic effect, and reactive oxygen species (ROS) for purpose of turning on some signal to induce necrosis and apoptosis in malignant cells. It is believed that using nano agents in combination therapy (chemotherapy, radiotherapy, and immunotherapy) can induce cell damage and improve radioenhancing and drug delivery and the immunogenicity abilities in the tumor site [10,11]. This fact supported many researchers to overcome existing barriers including limitations toward superficial tumor types, tumor cell targeting, and metastasis through the light therapy. This study covers major research achievements in photothemal-based combination therapy. Recently, to achieve high effectiveness cancer PTT, it is combined with chemotherapy, radiotherapy, immunotherapy, and gene therapy (Fig. 1).

Photothermal therapy (PTT)
Photothermal therapy (PTT) is a topical and minimally invasive treatment with low toxicity that has piqued the interest of academics recently [12]. This therapy can eliminate primary tumor cancer cells or local early-stage metastases and, when combined with other therapies such as chemotherapy, can reduce distant metastases in preclinical animals [13]. Generally, increasing temperature (41-43 • C ) in cancerous cells can inhibit the expression of metastasis-related factors such as vascular epithelial growth factor (VEGF), metalloproteinase (MMP-2/9) through the hyperthermia or PTT [14]. PTT's therapeutic effectiveness is greatly increased since heat generation is concentrated in the tumor tissue. According to researches, PTT caused cell death through the apoptosis rather than necrosis, due to the fact necrosis stimulates inflammatory responses, which might also additionally restrict anticancer effectiveness. This approach is serving as a healing technique that generally turns on the intrinsic apoptotic pathway that is a greater applicable and most potent cancer treatment [15,16]. Favorably, when PTT is used with other therapies, synergistic and amplified therapeutic benefits have the potential to be reached. This not only allows for an improvement in the overall effectiveness of cancer treatments, but also overcomes multiple drug resistance and hypoxia-related resistance in cancer treatment [17]. In order to attain a high therapeutic efficacy, PTT agents based on nanoparticles (NPs) are applied to achieve enhanced PTT. Because heat is only generated where NPs and active light are simultaneously present, it leads to exerting maximum damage to the target site and minimum damage to surrounding healthy tissue [18,19].

Application of NPs in PTT
One of the most benefits of using NPs in PTT is localizing NPs in the region of the tumor [20]. The capacity of using NPs in PTT application can be beneficial in some cases. Firstly, NPs are usually dispersed in biological fluids, and this issue improves the possibility of effective integration of NPs for appropriate concentrating delivery in targeted cells due to their longer circulation time in the bloodstream. Secondly, minimal adverse effects on the natural behavior of the host biosystem and efficient heat production during external excitation [21]. In addition, the enhanced permeability and retention (EPR) effect supports the accumulation of NPs in the tumors. However, a dense extracellular matrix (ECM) adversely decreases the deep penetration of NPs inside the growing cancer cells due to interstitial fluid pressure, which leads to low and uneven or peripheral accumulation.

Metallic NPs
The use of metallic NPs, photoluminance NPs, carbon-based nanomaterials, and natural and synthetic polymeric NPs in photothermal therapy is further described.

Gold NPs
As one of the photothermal agents, gold NPs (AuNPs) are a fascinating and popular nanomaterial in PTT due to their exclusive physical and chemical features, such as surface plasmon resonance (SPR) [22]. SPR is physical phenomena occurred in AuNPs. When metallic NPs are exposed to light, the electromagnetic field generates a coherent oscillation of the conduction band electrons of the metal and a bipolar oscillation along the electric field of light, which enhances optical feature such as absorption and scattering [23]. The absorption of AuNPs is highly dependent on the size, shape, and dielectric properties. By manipulating these factors through different synthesis methods, the absorption of AuNPs can be changed [24]. Therefore, AuNPs are able to vigorously absorb light and rapidly transform it into heat in order to kill tumors and prevent injury to surrounding healthy tissues [25]. Three factors including biocompatibility, thiol conjugation, and absorb NIR are most important issue in the using of AuNPs in PTT application [26].
In one research, Higbee-Dempsey et al. designed a nanoformulation that was particularly successful for breast cancer PTT and photoacoustic (PA) imaging under the NIR radiation. They showed that AuNPs with indocyanine green (ICG), a clinically-approved dye, in both in vivo and in vitro could be a promising therapeutic potential for triple-negative orthotopic breast cancer model therapy [27]. Li and et al. also designed ICG-loaded albumin − bioinspired gadolinium hybrid functionalized hollow gold nanoshells (ICG − Au@ BSA − Gd) for photodynamic and photothermal therapy in purpose of near-infrared fluorescence (NIRF)/PA/CT/MR imaging capability. The synthesized formulation exhibited prominent PA/CT imaging and T1-weighted MR signals, in addition to a remarkable NIR photothermal conversion capacity, excellent water dispersibility, and biocompatibility as shown in Fig. 2 [28].
In another study, Mendes et al. showed that using AuNPs and visible light in PTT could make doxorubicin (DOX) more destructive for breast cancer. They used this design and then subjected spherical AuNPs with a diameter of 14 nm under visible green laser light for breast therapy. They observed the effective conversion of light into heat and the noticeable death of cancer cells. As a result, a synergistic interaction between heat and the cytotoxic impact of DOX was revealed, which resulted in a reduction in the survival number of breast cancer cells as shown in Fig. 3 [29].

Iron oxide NPs
Iron oxide nanoparticles, often known as IONPs, are an excellent material choice for use in PTT. Because IONPs have excellent properties including biocompatibility, biodegradability, facile synthesis, and a unique contrast agent in magnetic resonance imaging (MRI) in clinical settings [30]. These NPs have the ability to absorb light throughout a broad spectrum, from the visible to the NIR, and convert the light energy into heat [31]. The mechanism of generated heat in IONPs is described through the Neel and Brownian relaxation relation by an alternating magnetic field (AMF) [32]. Changing direction of magnetic moments of IONPs in presence and absence of AMF leads to forming heat, which is used in hyperthermia [33]. Another kind of iron oxide NPs are superparamagnetic iron oxide nanoparticles (SPIONs) which is more colloidal stable in aqueous media by modifying. Similar to IONPs, these behaviors of NPs are defined by their ability to rapidly change the orientation of protons in their nucleus when exposed to an external magnetic field, resulting in extremely high levels of relaxation [34,35]. In a study, Khafaji et al. fabricated SPIONs coated with PEGylated silica and loaded both anti-cancer drug cisplatin and DOX as a dual drug delivery and MRI contrast agent system. Their result showed that under normal blood circumstances, both anti-cancer drug demonstrated a gradual release feature, which lowers toxicity and drug accumulation in normal tissues. SPIONs effectively delivered DOX and cisplatin to MCF-7 cells, resulting in anti-tumor properties. These NPs were also thought to be ideal MRI agents and to have high PTT efficacy. Both medicines were effectively released and shown robust function in photothermal-chemotherapy under the influence of pH and NIR light [36]. In another study, Sahbazi and his colleague synthesized IONPs with size of 7.36 nm and coated with polydopamine to evaluate the effect of PTT in melanoma cells (B16-F10) as well as in the mice model. According to their finding, this design was able to reduce 74% melanoma after the 4th time of treatment under the laser (λ = 694 nm, output power = 5 J/s) without any side effect [37]. Shin et al. also fabricated hydrogel containing dextran-coated iron oxide nanoparticles (DEX-IONP) for skin cancer treatment in both in vivo and in vitro models. The research findings in the B16F10 s.c. mice model showed that the topical PTT with DEX-IONP gel has the potential to drastically reduce tumor sizes. Notably, the development of the tumor could irradiation, (4) combined DOX + AuNPs + irradiation. Reproduced with permission from Ref. [29] with the permission of the Creative Commons Attribution 4.0 International License (http:// creat iveco mmons. org/ licen ses/ by/4. 0/). Copyright 2017, nature publishing groups be greatly suppressed by 85% via the use of a single PTT treatment with 100 µgFe/mL DEX-IONP gel and 0.5 W laser intensity for 10 min. [38].

Photoluminance NPs
The poor depth of penetration of lasers is able to limit PTT. One efficient strategy for expanding the penetration depth is to pick a biological window that is appropriate for the situation and then to make the light source's wavelength even longer. Upconversion NPs (UCNPs) have unique antistokes luminescence features and offer significant potential in the field of phototherapy. These traits are a direct result of the 4f energy level of the lanthanides. UCNPs have the ability to emit short-wavelength light when excited by longwavelength light, which helps to strike a balance between the depth of penetration and the therapeutic impact. UCNPs provide a dilute guest system, which allows lanthanides to be doped with activators. As the luminous center of the system, lanthanides have abundant long-life energy levels, which is the key to the cascading absorption of multiple low-energy photons (long wavelength) and release of high-energy photons. Therefore, the UCNPs can perform the role of a transducer that is capable of converting NIR light to visible light. This issue plays an important role in photosensitizers for the generation of active oxygen in order to activate caspase 3/7 leads to apoptosis in PDT [39,40]. In a study reported recently by the Chattopadhyay group for the purpose of multimodal imaging-guided synergistic PTT and PDT at the targeted tumor site, nanoformulation (NaGdF4:Yb,Er (UCNP)) has been designed by anchoring human transferrin protein (Tf) and loading Rose Bengal (RB) to form UCNP@Tf-RB. It was evaluated under power (0.32 W/cm 2 for 7.5 min) both in vivo and in vitro. This design not only combined PTT and PDT for therapy of 4T1 tumors but also provided circumstances in both active and passive targeting as well as dual-modal imaging (MRI/photothermal), with high biocompatibility and stability. This group showed tumor growth inhibition index (TGII) of the suggested design for combination therapy (PDT/PTT) was 0.91 while TGII for PTT only was 0.79%. This achievement revealed overcoming synergetic therapy (PTT + PDT) compared to solitary therapy (PTT) [41]. Yan et al. also provided molecularly imprinted UCNPs (UCPs@MIPs) as a microinvasive PTT and an artificial antibody for active targeting against the HepG2 tumor and MCF-7 cells. This group for evaluating the efficacy of PTT used a 980-nm NIR laser beam (4.0 W/cm 2 ) at various times. Their findings demonstrated that UCP@MIPs have exceptional capabilities, such as multicolor UCNP fluorescence, the capacity for rapid heating (in 2 min reaching 45 • C ), and an outstanding capacity to target tumors [42].
Quantum dots (QD) contain photoluminescence NPs have been used in the field of phototherapy due to their smaller size than the Bohr exciton radius and quantum confined effects. This effect allows to researchers adjust the optical properties of QD for controlling the size for biological requirements. Both fast metabolic rate and efficient ROS generation are the most important factors, respectively, avoiding long-term toxicity and leading to the apoptosis pathway. Black phosphorus QD (BPQDs) as a novel photothermal agent showed an appropriate biodegradable, great light stability, and a large extinction coefficient feature. Interestingly, phosphorus material can be used in PDT as a photosensitizer. For instance, Sun et al. found that a relatively small quantity of BPQDs (50 ppm) is adequate to destroy almost all tumor cells when exposed to an 808 nm laser. Favorably, high concentrations of BPQDs did not have toxicity in lack of laser radiation [43]. In the other study, Liang utilized BPQDs with remarkable NIR photothermal properties and photothermally increased glucose oxidase (GOx)-like activity in an acidic tumor microenvironment. This group, after membrane isolation of red blood cells and binding iRGD peptide (penetrating tumor agent), evaluated iRGD-RM@ BPQDs under the 808-nm NIR laser (1 W/cm 2 ) in vivo and in vitro. Their results suggested iRGD-RM@ BPQDs + NIR could efficiently generate ROS within cells. Moreover, the engineering of BPQDs could show a photothermal conversion efficiency of 28.9% and rapidly reach 50 °C [44].

Carbon-based nanomaterials
Carbon nanotubes have the ability to absorb light energy very efficiently in the biologically transparent window (750-1000 nm) and generate heat through a process called non-radiative relaxation. Single or multi-coaxial tubes were made of sp 2 carbon atoms, and they are classified as either single-walled carbon nanotubes (SWCNTs) or multi-walled carbon nanotubes (MWCNTs) as well. Carbon nanotubes are capable of successfully loading drugs thanks to the aromatic ring and delocalized p electrons inside their structure. After modification, the carbon nanotubes exhibit longer blood circulation times that are suitable for drug delivery and showed significant biocompatibility [45]. Favorably, carbon nanotubes have also a curative impact on tumor metastasis. Liang et al. utilized SWCNT-based PTT to eliminate metastatic cancer cells in sentinel lymph nodes, which are key organs for cancer metastasis. They showed that the concentration of SWCNTs in sentinel lymph nodes increased 20 min after injection into the main tumor due to lymphatic drainage. The sentinel lymph nodes had the most SWCNTs 90 min after injection, and their signal was five times higher than the muscles. Then, this group injected SWCNTs intratumorally and tumors were irradiated to confirm that SWCNTbased PTT inhibits tumor spread. The treated group survived longer than the control group, whose sentinel lymph nodes 1 3 were not exposed to light [46]. Graphene, a two-dimensional honeycomb lattice nanostructure of carbon atoms, has been used in many biomedical applications. However, using graphene-based material in biomedical suffer from poor dispersion in the biological environment, irreversible aggregation, and potential cytotoxicity. In a study, the Chiang group synthesized reduced graphene oxide (rGO) and then coated it with PEGylated chitosan as a novel reducing and stabilizing agent to form (PCS-rGO) nanosheets for PTT. Importantly, under 808 nm irradiation, this designed nanosheet shows high photothermal conversion efficiency (67.7% vs. 55.0%).
In vitro experiments on cell uptake and cytotoxicity showed that PCS-rGO nanosheets were able to kill cancer cells when NIR caused them to heat up (above 49 °C), showing that they have a lot of potential in cancer PTT [47].

Polymeric nanoparticles
Researchers have been interested in using natural polymeric materials (like polydopamine, melanin) and synthetic polymeric materials (like poly-L-lactic acid, polyethylene glycol, polyaniline, etc.) in biomedical fields [48,49]. Because of their biocompatibility, biodegradability, and their photothermal conversion efficiency, these polymeric materials appear to be suitable candidates for use in PTT. Using multifunctional polymeric nanocarriers, it is possible to overcome the limits of NIR adsorbents in line while boosting their efficiency in PTT. Physical mechanisms, covalent or coordinate bonds, and electrostatic interactions can all be used to insert NIR adsorbents into polymer nanocarriers [50,51].

Natural polymeric NPs
Hyaluronic acid (HA) is one of the most popular natural polysaccharides [52]. The negative-charged hydrophilic natural polymer can be combined with NIR dye like indocyanine green (ICG), to provide an amphiphilic prodrug. Due to its natural propensity to bind to the CD44 receptor, which is overexpressed in many cancer cells, HA is able to specifically target these cells and killed through NIR [53]. However, the direct application of the NIR dye IR780, which is used for PTT and imaging, is restricted by its high cytotoxicity and low solubility in water. That is why Alves et al., as a pioneer group, employed IR780 and DOX-loaded amphiphilic HA nanoparticles (HPN) to treat breast cancer. Light at 808 nm was better absorbed when IR780 was encapsulated in HPN, and the findings revealed that cell compatibility and PTT potential were also enhanced. In vitro 2D cell uptake tests showed that breast cancer cells were more likely to take up the produced nanostructures than normal cells. Additionally, the therapeutic benefits of NIR and IR/DOX-HPN were amplified by their combined effects on reducing the survival of cells [54]. In another study, for the combination PTT-chemotherapy treatment of breast cancer, Yang et al. designed a multifunctional NPs as attaching the reductionresponsive camptothecin (CPT) to Prussian blue NPs (PB NPs) and then modifying it with the tumor-targeting RGD cyclic peptide and HA which showed low systemic toxicity and promising treatment for cancer therapy by irradiation with 808 nm laser [55].
Human serum albumin (HSA) and bovine serum albumin (BSA) are the most common proteins which used as delivery vehicles. Using these kinds of proteins are very beneficial for ICG transmission, due to their biocompatible, stable, nonimmunogenic, and non-toxic properties as well as targeting tumor through the interacting with the gp60 receptor and Secreted Protein Acidic And Cysteine Rich (SPARC) [56,57]. Fortunately, albumin NPs not only increase photoluminescence quantum yield (PLQY) but also have a proper hydrophobic interaction with ICG. In the related study, the optimized ICG-BSA nanostructure for the PTT application showed a high PLQY and a passively targets better than free ICG. This design could improve NIR fluorescence imaging of PTT in the treatment of triple-negative breast cancer (TNBC) [58,59]. In the same direction, Shen et al. used HSA with ICG and D-tocopherol succinate (TOS) for delivering DOX in the 4T1 cell line (mouse breast cancer) and liver HL-7702 cancer cells [58].
The polydopamine (PDA) often is produced by the oxidative self-polymerization of the catecholamine known as dopamine and has garnered a lot of interest in some reports [60,61]. PDA-based designing exhibited significant optical absorption and stability to activate PTT agent, good biocompatibility, biodegradability, pH sensitivity, and water solubility feature [62,63]. In tumor sites under NIR laser, PDA is not only able to successfully cause hyperthermia and thermal erosion but also can operate as a drug carrier by capturing the drug through either a physical binding or a hydrogen bond [64]. The photothermal conversion efficiency of PDA is greater (20-40%) than that of many other PTT agents. So, it is believed to be an appropriate PTT agent for the treatment of cancers [65].

Synthetic polymer NPs
Polypyrrole (PPy), an organic conductive polymer, has been utilized in several biomedical applications. PPybased NPs with the desirable traits can be synthesized by a simple self-assembly process. Biocompatibility, high absorption in the NIR range, high light stability, high photothermal conversion efficiency, and low toxicity are some properties of PPy that make it permissible for PTT application [63,64]. Tran and his colleagues used PPy NPs to make a platform for a targeted binding site for the CD44 receptor through the using the IR-780 into a PLGA core with HA shells around it to provide IPPH. ROS and heat generation through IPPH prevented cancer cell survival after NIR laser irradiation. In vivo and in vitro research suggests the synergetic effect of PTT and PDT for treating breast cancer [66]. Song et al. coated IONPs with PPy and PEG to form the IONP@PPy-PEG to assess PTT effectiveness after injecting nanocomposites intravenously into mice with 4T1 tumors. MR and photoacoustic (PA) imaging of the provided nanopaltform demonstrated substantial accumulation in the tumor site 24 h after injection. Thus, the generated IONP@PPy-PEG nanoplatform showed great imaging and cancer therapy potential [67]. Nguyen et al. integrated rapamycin and PPy NPs PEGylated liposomes for the purpose of treating cancer in a specific manner. The liposomes were then conjugated with trastuzumab monoclonal antibody, to form LRPmAb. Due to the fact that drug release from this design was dependent on pH, NIR laser irradiation had the potential to boost it. Because of their increased expression of HER2/neu receptors, breast cancer cells' uptake is greater than normal cell types. Irradiation with NIR lasers has a substantial inhibitory effect on each and every breast cancer cell. As a consequence of this, the synergistic therapy of LRPmAb was validated even further by the observation of cell apoptosis, nuclear degeneration, and anti-proliferation, all of which have the potential to be useful in the treatment of breast cancer as shown in Fig. 4 [68].
Poly (lactic-co-glycolic acid) (PLGA) expanding use in biological domains like as molecular imaging, drug delivery systems, and PTT is another item from synthetic polymer NPs for its high biodegradability and biocompatibility [69,70]. Interestingly, the body hydrolyzes copolymers to metabolites like glycolic acid and lactic acid, which may ultimately be catabolized to CO 2 and H 2 O in the Krebs cycle. This fact is favorable in using PLGA due to their low toxicity and side effects [71]. PLGA's core-shell structure and ability to coencapsulate hydrophilic and hydrophobic components make it an efficient biomedical nonoformulation platform. For instance, PLGA NPs potentially incorporated IR780 iodide as a photothermal conversion agent for cancer therapy [72].  age size, PDI, and zeta potential of prepared material, d drug release profile in different pH after irradiation with NIR 808 nm laser (2 W/ cm 2 , 2 min), e TEM result of prepared sample. Reproduced with permission from Ref. [68]. Copyright 2017, Elsevier [73]. Favorably, when PLGA is coated on carbon nanodots, it not only increases the loading capacity of the drug, but also prolongs its release time as well as a promising performance in red fluorescence and PA imaging [71].

Advantages and disadvantages of PTT
PTT has benefits over traditional treatment methods. First, PTT can accurately manage treatment area, time, and effectiveness by adjusting irradiation location, duration, and power though targeting different NPs and remote controlling from outside of the body in a murine modal. As a consequence of these aforementioned reasons, it is facile to make quick adjustments to the treatment approach in accordance with the clinical requirements. Second, the synergetic effect through PTT with other treatment methods like PDT, radiotherapy, chemotherapy, and immunotherapy showed the exciting result. However, low penetration of using UV and NIR laser in tissue (usually lower than 1 cm) in animal modeling and clinical phase due to the high absorption of water molecules in biological windows can be a serious problem in achieving to the effortful treatment in PTT. To eradicate these barriers, utilizing combination therapy can be a logical and promising treatment methods nano-medicine and biotechnology field in favor of cancer therapy in the future.

Combined phototherapy
A single modality of treatment is inadequate for practical cancer treatment application. The use of PTT in combination with other therapeutic approaches offers a more effective treatment choice.

Combination with chemotherapy
Researchers have been working on producing anticancer medications utilizing small molecules since the early 1900s. Chemotherapy has been the most often employed modality in oncological research [74]. On the other hand, chemotherapy has a number of intrinsic adverse effects owing to the fact that it cannot selectively target tumors, and it often results in inadequate treatment, which may lead to cancer recurrence and drug resistance. Relatively recent research has emphasized on the use of chemotherapy in combination with phototherapy to overcome the challenges. However, simultaneously presenting a more therapeutic impact, nanosystems provide a possible solution to the problems that are caused by chemotherapy [75,76]. It is essential to have a delivery method through the nanocomposite that is both safe and effective in order to achieve sufficient therapeutic results. Nanocomposites are the most important aspect of this combination for improved chemotherapy. When it comes to the targeted delivery of small anticancer drugs to tumors in a selective manner, it can act as both a PTT agent and nanocarrier at the same time. Using nanocarriers for doxorubicin (DOX) and camptothecin (CPT) delivery has developed an effective and safe method with the aid of active and passive targeting abilities. The mechanism of passive targeting is based on the EPR effect. According to this fact, NPs can readily pass across cells due to aberrant vascular structure.
As a multifunctional nanoplatform for combined photo and chemotherapy, Zhang et al. prepared porphyrin-based metal-organic framework-coated gold nanorods (AuNR@ MOFs@CPT). It has garnered a lot of interest as potential drug delivery systems due to the promising construction of porous materials. MOFs not only integrate photosensitizers inside their arrays but also provide a condition for drug encapsulation due to having large pore sizes and high surface areas. Therefore, loading efficiency, which is a limiting issue in conventional combination treatment, is developed through employing MOFs, which are multifunctional organic frameworks. Their finding showed that AuNR@MOFs@CPT improved the therapeutic effect on tumors under irradiation with an NIR (808 nm) and displayed proper CPT accumulation in the tumor site as shown in Fig. 6 [77]. Attari et al. also provided silicacoated Fe 3 O 4 loading with curcumin, an anti-cancer drug, as a dually functioned nanocomposite for the treatment of breast cancer model in Balb/c mice in PDT (irradiate diode laser at 450 nm) and PTT (irradiate diode laser at 808 nm). Their result showed that the expression of apoptotic factors, including Bax and Caspase3, increased significantly in this design. In addition, there were no harmful effects of the treatment found in the mice's vital organs like the liver and lungs, which is a problem with some traditional therapies in chemotherapy as shown in Fig. 7 [78]. In spite of the advancement in drug delivery systems through the passive targeting, it is difficult to deliver accurately the needed dose of drug in tumors. Burst release unfavorably makes side effects due to the off-target function of chemotherapeutic drugs. It seems that using active targeting may be beneficial in increasing the efficiency of drug delivery and targeting drugs. Pan group designed selective drug delivery to the tumor and not to normal cells for precision and accurate delivery of DOX into the breast cancer cell line (MCF-7) through modifying the phenylboronic acid (PBA) group on the surface of PDA@CP-PEG. Sialic acid (SA) is overexpressed in metastatic cancer cells which are able to bind existing PBA on PDA@CP-PEG to facilitate active targeting. They also demonstrated PDA@CP-PEG had a remarkable in vivo antitumor effect, which is a potential candidate for the clinical use [75].

Combination with immunotherapy
James Allison and Tasuku Honjo won the 2018 Nobel Prize in Physiology and Medicine for their work on immune checkpoint blockers and cancer immunotherapy. Cancer immunotherapy trains antitumor immune cells in the tumor microenvironment and uses lymphoid immune cells to eradicate tumor cells. Systemic immune monitoring cannot only eliminate local and metastatic tumor cells but also may prevent tumor recurrence in long-lasting immunological memory. Utilizing phototherapy and PTT can stimulate a systemic antitumor immune response in target cancer cells. In fact, phototherapy is a suitable treatment option that to change cold tumors, induce limited immune response, into hot tumors [79]. In this issue, photothermally-mediated tumor immunotherapy strategy based on a transdermal delivery system was disclosed by Ye et al. through microneedles patch. Melanin in the patch generates heat and boost antitumor immune response under NIR light [80]. In other study, Liang et al. coated erythrocyte membranes (RMs) on BPQDs due to inducing the apoptosis in situ under NIR irradiation in favor of activating immune response. Favorably, suggested designing could accumulate in tumor and show prolong blood circulation as well [81]. Insufficient oxygen and lymphocytic infiltration in the deep and internal tumors make a restriction in efficacy of sensitizing tumors to immune checkpoint inhibition in low temperature [82]. Shen et al. used Chinse ink, an azo-initiator of 2,2-azobis[2-(2-imidazoline-2-acyl)propane]dihydrochloride (AIPH), to induced a high expression programmed cell death protein-ligand 1 (PD-L1) in tumors through generating alkyl radicals upon NIR-II laser irradiation. The alkyl radicals augmented the immunogenic cell death (ICD) and increased the recruitment of tumor-infiltrating lymphocytes which consequently change cold tumor into hot tumor as shown in Fig. 8 [83]. For increasing treatment efficacy of PTT, using anti-cancer drug accompanied with PD-L1 immune response may be a better idea. It is worth mentioning, chemotherapeutic drugs (Dox) work within tumor cells, whereas immune checkpoint (ICP) inhibitors work outside of the cells. Favorably, pickering nanoemulsion (PNE) is an oil/ water interfacial stabilizer that was designed by Yang et al. employing multi-sensitive nanogels with pH-responsive, hydrophilicity-hydrophobicity switch, and redox-responding capabilities. Their designing appeared an appropriate releasing of DOX and HY19991 in the tumor microenvironment, enhanced tumor penetration of DOX, antitumor efficacy, and the strong immune response in vitro and in vivo [84].

Combination with radiotherapy
Ionizing radiation with a high energy level, such as X-rays or γ-rays, can be used to ionize water and other components of cells, which results in the production of ROS, which can damage DNA and cause apoptosis. Radiotherapy is one of the common therapeutic approaches in the field of tumor Unfavorably, light only superficially penetrates tissue, and single-mode phototherapy is not an effective method for treating cancer that has spread throughout the body. However, the ionizing X-rays used in radiation therapy have an impact on tumor tissue that allows them to penetrate deeper into the tumor, which may destroy tumor cells properly. In PTT, increasing temperature improves blood flow and stimulates ROS formation, which enables a lower dosage of potentially damaging X-rays to be administered. It means that it is possible to increase the therapeutic effectiveness while simultaneously reducing the adverse effects on the healthy tissues that are located nearby the tumors. Cancer therapy with the combination of radiation and phototherapy can be a promising procedure in the future. Generally, radiotherapy suffers hypoxia (lack of oxygen) in the treatment process. Fortunately, PTT is not restricted to a hypoxic environment inside the tumor and has the ability to eradicate tumor cells that are resistant to radiation. Additionally, the oxygenation state inside the tumor may be improved by the elevated intratumoral blood flow that is caused by the photothermal. For instance, Song et al. used hollow Bi 2 Se 3 NPs for the purpose of enhanced radiotherapy with PTT. Pegylated-Bi 2 Se 3 was utilized to load perfluorohexane (PFC), as an oxygen reservoir to make up hypoxia in radiotherapy after exposing NIR light. The PEG-Bi 2 Se 3 @PFC@O 2 + NIR treatment group showed the fewest hypoxic signals, demonstrating an effective source of oxygen in combination PTT with radiotherapy [85]. Similar to this idea, Yang group used a red blood cell membrane (RBCm)-camouflaged, red blood cell content(RBCc), and the copper sulfide(CuS) for exogenous oxygen supply, photothermal, and radiosensitization aims. CuS has a good absorption in 980 nm that leads to converting light energy to heat in situ in murine mammary carcinoma cell [86]. Li et al. examined the NIR-induced synergetic therapeutic effectiveness using an organic semiconducting pronanostimulant (OSPS) consisting of an immunostimulant and semiconducting polymer NPs bonded by a 1 O 2 -cleavable linker [87]. Since radiotherapy has a good potential for the treatment of cancer located in the deeper part of the body from the skin (> 1 cm), it can be useful in combination with PDT. Scintillator as down convert X-ray radiation can provide the required energy for activating photosensitizers. This allows for efficient X-ray radiation-induced photodynamic therapy. Scintillators are a kind of NPs to transform the X-ray photons into many electron-hole pairs, which subsequently transmit their energy to the luminescent ions. After the luminescent ions return to their ground state, UV-Vis light is released to activate the nearby photosensitizers for PDT. GdEuC1 2 , SrAl 2 O4:Eu 2+ , and Tb 2 O 3 are some of the cases in this category which activated under X-ray in the energy range keV or MeV [88]. For instance, bismuth oxyiodide (BiOI) as a radiosensitizer with high-Z elements in I and Bi atoms was designed by the Gue group to be served as an X-ray-induced photosensitizer in the purpose of ROS generation. Interestingly, Bi 2 S 3 coating on BiOI improves electron-hole pair production to reduce recombination, resulting in increased photocurrent as semiconductor heterojunction NPs (SHNPs) shown in Fig. 9 [89].

Combination with gene therapy
Treatments based on NPs have a potential in the cancer therapy because of focusing on active and passive targeting and using them as a carrier in drug delivery. Genetic agents can be transported via NPs for enhancing the therapeutic benefits of gene therapy in different strategy including gene-regulated enzyme prodrug therapy, oncolytic viral vectors, hypoxia-induced gene expression, sensitization, and application of replication-competent. Photo-response agents loaded with shRNA, siRNA, microRNA, cas13a, and cas9, as gene editing items, can be used for effective combination treatment based on the synergistic anticancer effects of phototherapy and gene therapy [90]. Another usage of a combination of gene therapy with phototherapy is regulating the expression of hypoxia-inducible factor-1a (HIF-1a) and VEGF to improve treatment efficacy in a safe procedure and low toxicity in PDT [91,92]. One of the benefits of mild PTT is providing a condition for increasing penetration of NPs through cell membrane due to employing of low power photothermal irradiation. Therefore, nanocarriers deliver microRNA into cells, regulating target genes as a photocontrolled gene transfer application [93]

Conclusions and perspectives
In comparison to the high-energy ionizing radiation treatment and chemotherapy, the exposed radiation from phototherapy is relatively low in intensity and show minimal side effect, which persuades researchers to use it as an environmentally friendly method of treatment. This review brought up a novel and sophisticated treatment for increasing the efficacy of PTT through metal NPs, photoluminance NPs, carbon-based nanomaterials, and polymeric NPs in the NIR range in favor of increasing temperature in situ and then clarified different barriers in chemotherapy, radiotherapy, immune therapy, and gene therapy including inadequate drug delivery, hypoxia, limited immune response in a cold tumor, and gene silencing respectively. Irradiation of a tumor with a laser in the presence of a photosensitizer could have a local therapeutic effect that might eventually result in the major treatment of the tumor. For an appropriate combination, the temperature must be carefully addressed. Radiotherapy is not a very effective method for treating hypoxic cancers due to their lack of oxygen in their cells. This restriction does not apply to PTT, which is an efficient method for ablating hypoxic tumors. Due to the high energy of radiation, this treatment modality is able to operate on deep-seated cancers, while phototherapy is only effective on the skin's surface. As a result, the combination of phototherapy and radiation is essential for improved synergistic therapeutic effectiveness. Combination with gene therapy increases the effectiveness of cancer treatment while simultaneously lowering the risk of off-target negative effects. In addition, gene therapy is distinct from conventional therapeutic approaches because it makes primary use of the body's innate ability to fight cancer, restoring the equilibrium of the internal environment, and is the most recent treatment strategy based on the immune system's ability to combat cancer. However, the therapy is slow and time-consuming due to limitations such as the limited controllability of in vivo gene expression, the low effectiveness of gene transfer, and the instability of genes. Therefore, taking into consideration the drawbacks in the control group (PBS) and treated group (SHNPs) under the 808 nm laser irradiation (1 W/cm −2 ). Reproduced with permission from Ref. [89]. Copyright 2017, Wiley of phototherapy and the limits of other therapeutic modes, combination methods offer an encouraging treatment strategy that is appropriate for practical use. The advancement of nanotechnology will result in a further improvement of the interaction between the various treatment modalities and will assist in the development of promising combination therapies that have the ability to cure cancer.