Figure 3. Schematic illustration of (a) synthesis route of mPEG(CO) and (b) the nanobomb consist of mPEG(CO) and PBPTV. (c) MPTT process of nanobomb. (d) UV absorption (blue) and fluorescence emission (red) spectra of the aqueous nanobomb solution. (e) The temperature rise curve under 808 nm NIR irradiation. (f) The change of UV spectrum shows the release of CO in the aqueous nanobomb solution tested by reduced hemoglobin. Reproduced from Ref. [122] with permission. Copyright 2022 Wiley-VCH.
3.2. Inorganic materials
Inorganic nanomaterials represent a large class of PTAs employed in tumor PTT. Currently, the realm of inorganic PTAs encompasses noble metal NPs, metallic chalcogenide nanomaterials, carbon-based nanomaterials, magnetic NPs, and QDs etc.[24, 123-125] These inorganic PTAs boast a range of exceptional attributes including robust NIR light absorption capabilities, high PCE, facile preparation and modification processes, often coupled with other advantageous properties enabling their utilization in fluorescence imaging, PAI, or nuclear magnetic resonance imaging (MRI).[126-128] Nevertheless, inorganic PTAs also present certain limitations, notably suboptimal biocompatibility and challenges associated with biodegradation. As a result, enhancing the biocompatibility of inorganic PTAs to facilitate their metabolism within the human body and mitigate their potential long-term toxicity has emerged as a crucial focal point in the application of inorganic nanomaterials for tumor PTT and related research endeavors.
3.2.1. Noble metal nanomaterials
From the end of the 20th century to the present, the research on noble metal nanomaterials has changed rapidly. For instance, the researchers found that nano-gold has excellent catalytic properties, which breaks the stereotype that bulk gold is chemically inert. Besides, noble metal nanomaterials exhibit good electrical conductivity, thermal conductivity, and reflectivity.[129-131] Noble metal nanomaterials also exhibit unique properties and have demonstrated their capabilities in catalysis, medicine, biology, imaging, optics, and other fields. Qu et al. presented a pioneering approach involving the synergistic manipulation of the TME by enhancing the activation of a fever-mimic response. This innovative strategy combines MPTT with tumor vascular normalization. The implementation of this engineering concept was achieved through a fever-inducible lipid nanocomposite denoted as GNR-T/CM-L. This nanocomposite generated mild heat at approximately 43 °C and subsequently released multiple components upon NIR irradiation. This orchestrated process synergistically upregulated interferon-gamma, establishing a bidirectionally closed loop.[132] This loop promotes M1 polarization of tumor-associated macrophages, consequently inhibiting tumor growth downstream. You et al. employed core-shell structured Au@SiO2 nanomaterials boasting high photothermal performance to devise a groundbreaking strategy. This innovative approach entailed the integration of photothermal conversion nanomaterials with heat-triggered nitric oxide (NO) donors (RSNO) within a nanoplatform. This integration led to the realization of MPTT that synergistically enhances NO gas therapy under NIR radiation. 2-phenylethynesulfonamide (PES), an inhibitor of HSP70, was ingeniously loaded into the NO nanogenerators to facilitate effective MPTT. The outcomes revealed a significant enhancement in the synergistic effect of MPTT and gas therapy, achieved through controlled NO release under NIR-mediated conditions.[133] This study not only unveils a strategy to achieve gentle photothermal therapy by inhibiting HSP70 expression but also introduces a novel approach for controlled NO release. Most significantly, this research underscores the substantial potential of multifunctional therapeutic agents in driving synergistic cancer treatment methodologies. Wang et al. meticulously devised and synthesized gold nanocages (GNCs) that were ingeniously functionalized with primary macrophage membrane and surface anti-PDL1 antibodies, while also being loaded with the TGF β inhibitor galunisertib. GNC-Gal@CMaP nanocomposites effectively executed MPTT and induced immunogenic cell death (ICD), subsequently bolstering the anti-tumor effectiveness of both anti-PDL1 antibodies and galunisertib. This enhancement was achieved through the activation of antigen-presenting cells, which in turn primed tumor-specific effector T cells.[134] This study conclusively demonstrates the experimental viability of combining immunotherapy with MPTT for combatting colorectal cancer. Dong et al. embarked on an exploration of an innovative antimicrobial nanosystem, denoted as Dap@Au/Ag nanorods (Dap@Au/Ag NRs), which relies on gold nanorods as its foundation. The study delved into the antimicrobial attributes of this groundbreaking agent using methicillin-resistant Staphylococcus aureus (MRSA) as the experimental strain. In the presence of hydrogen peroxide (H2O2), Dap@Au/Ag NRs effectively release silver ions and antimicrobial peptides (Dap). This dual action disrupts the integrity of the MRSA membrane, culminating in content leakage and eventual bacterial demise.[135] Notably, compared to conventional PTT, employing laser irradiation with an appropriate intensity at the initial stages of infection, while maintaining a mild temperature, not only substantially curbed MRSA growth, prevented extensive wound ulceration, and fostered wound healing but also averted notable thermal damage to the wound site and surrounding skin. Qi et al. introduced an innovative solution by creating a platelet membrane (PM)-coated mesoporous Fe single-atom nanozyme (Fe-SAzyme). The resulting PM-coated mesoporous Fe-SAzyme (PMS) exhibited commendable attributes, including satisfactory NIR-II photothermal performance, high peroxidase (POD) activity, and effective tumor-targeting capabilities. Additionally, PMS exhibited potential as a carrier for protein drugs due to its internal mesoporous structure. In vitro experiments demonstrated that PMS effectively inhibited the expression of HSP by inducing mitochondrial damage, ultimately enhancing the efficacy of MPTT.[136] This study is pioneering in its application of a biomimetic mesoporous Fe-SAzyme to achieve mitochondrial damage-mediated MPTT. Notably, it presents a novel avenue for designing additional SAzyme-based systems for cancer treatment, representing a promising step forward in the field. Wang et al. devised a cascade potentiated nanomodulator named AuPtAg-GOx, designed to amplify immune responsiveness. By harnessing 1064 nm laser irradiation, MPTT triggered by AuPtAg activates cytotoxic T lymphocytes while simultaneously reversing the immunogenically ”cold” tumor microenvironment. To further enhance the thermal sensitivity of tumor cells, GOx played a dual role: it suppresses the production of heat shock proteins, thereby facilitating MPTT, and it collaborates with AuPtAg nanozymes, which possess catalase-like activity. This collaboration effectively alleviates tumor hypoxia, leading to a significant enhancement in GOx activity. The strategic combination of AuPtAg-GOx with its self-augmented photothermal capacity, alongside PD-L1 antibody, results in an elevated antitumor efficacy.[137] This approach encompasses a synergistic cascade of starvation therapy, MPTT, and immunotherapy enhancement through AuPtAg-GOx. This sophisticated strategy offers a promising avenue to efficiently eliminate cancer cells.
3.2.2. Metallic compound
Two critical limitations that impede the therapeutic efficacy of MPTT is that the constrained penetration depth of PTAs within the NIR-I biowindow and the thermoresistance engendered by HSPs.[138, 139] To surmount these challenges, Cao et al. introduced an innovative strategy termed nucleus-targeted MPTT, operating within the NIR-II region. This strategy achieves potent tumor eradication by synergizing vanadium carbide QDs (V2C QDs) as efficient PTAs with an engineered exosome (Ex) vector. The V2C QDs, adept at photothermal effects in the NIR-II region, are modified with TAT peptides and encapsulated within Exosomes bearing RGD modifications (V2CTAT@Ex-RGD). These resulting NPs exhibited commendable biocompatibility, prolonged circulation times, and the capability to escape endosomes. Notably, they can specifically target cells and translocate into the nucleus, enabling the realization of MPTT characterized by heightened tumor destruction efficiency. Furthermore, the NPs boast additional functionalities such as fluorescent imaging, PAI, and MRI.[140] This nucleus-targeted MPTT strategy within the NIR-II region represented a promising step toward the successful clinical implementation, offering newfound possibilities for advanced cancer treatment. Song et al. presented a pioneering study wherein Bi2Se3 hollow nanocubes (HNCs) are ingeniously synthesized using a mild cation exchange approach and the Kirkendall effect. Subsequently, these HNCs are modified with HA via a redox-cleavable linkage (-S-S-), affording the HNCs the ability to specifically target cancer cells with overexpressed CD44 receptors, while also enabling controlled cargo release. Notably, GA, an HSP inhibitor crucial for mitigating cellular damage caused by heating, is loaded into the Bi2Se3 HNCs. This novel construct, termed HNC-s-s-HA/GA, when subjected to mild NIR laser irradiation, effectively triggered cancer cell apoptosis. This process achieved MPTT with outstanding efficiency in inducing cancer cell damage. Furthermore, the enhanced radiotherapy (RT) potential of the construct is also demonstrated, facilitated by the presence of the RT sensitizer Bi2Se3 HNC. This research introduces a straightforward method to synthesize Bi2Se3 HNC-s-s-HA/GA possessing both theranostic functionality and cancer cell-specific targeting via glutathione (GSH).[141] Liu et al. introduced a novel approach involving the development of ultrasmall chitosan-coated NPs (CS-RuO2 NPs) possessing inherent nuclear-targeting attributes for NIR-II MPTT. Ruthenium(IV) oxide NPs (RuO2 NPs) were synthesized using a straightforward one-pot synthesis method. Exploration into NPs with varying sizes and surface charges revealed that only those exhibiting both an ultrasmall size and a positive charge could effectively penetrate the nucleus.[142] Wu et al. devised a biodegradable nanotheranostic agent by utilizing hollow mesoporous organosilica NPs, encapsulating a HSP90 inhibitor. Subsequently, they engineered the pores by gating with bovine serum albumin-iridium oxide nanoparticles (BSA-IrO2) and conjugating PEG, culminating in the creation of 17AAG@HMONs-BSA-IrO2-PEG (AHBIP) nanotheranostics. This multifaceted platform facilitates multimode computed tomography (CT)/PAI-guided PDT and MPTT. The nanoplatform exhibits remarkable PCE, high cargo loading (35.4% for 17AAG), and responsive release of 17AAG to inhibit HSP90. Additionally, IrO2 imparts catalytic activity to the nanotheranostics, promoting the breakdown of H2O2 into O2, thus mitigating tumor hypoxia and protecting normal tissues from H2O2-induced inflammation.[143] The resultant synergistic PTT/PDT enabled by AHBIP demonstrates exceptional therapeutic outcomes both in vitro and in vivo. The amalgamation of BSA-IrO2 and biodegradable HMONs within this nanoplatform showcases significant potential for future clinical applications. Cai et al. innovatively engineered and synthesized hollow-structured CuS NPs as carriers for the ataxia telangiectasia mutated (ATM) inhibitor, resulting in CuS-ATMi@TGF-β NPs. These NPs exhibit exceptional photo-stability, controlled drug release, and the ability to efficiently elevate the temperature upon NIR irradiation. Significantly, CuS-ATMi@TGF-β NPs possessed a remarkable tumor-targeting capacity, leading to substantial suppression of tumor growth.[144] Cai et al. devised a streamlined one-pot method to exfoliate and concurrently functionalize single-layer MoS2 nanosheets, utilizing bovine serum albumin template gadolinium oxide (BSA-Gd2O3) NPs as the exfoliant and MRI T1 contrast enhancer. Building upon this foundation, hyaluronic acid (HA) was subsequently linked to facilitate targeted interaction with cancer cells exhibiting CD44 overexpression. Subsequently, the natural HSP90 inhibitor GA, was loaded onto the platform. This novel configuration proved effective in reducing the heat resistance of tumor cells, enabling MPTT at a moderate temperature threshold. The investigation encompassed comprehensive in vitro and in vivo evaluations, affirming the exceptional biocompatibility of the GA/MoS2/BSA-Gd2O3-HA nanocomposite. Furthermore, the study demonstrated high potential for application in combined MPTT and chemotherapy, with the added benefit of MRI guidance.[145] Dai et al. meticulously executed a gentle phototherapy strategy to validate their hypothesis. They ingeniously devised foam cell-targeted nanoprobes capable of enabling MPTT and/or PDT through the integration of hyaluronan and porphine onto black TiO2 NPs. when executed below 45 °C, remarkably diminished intracellular lipid burden devoid of inducing overt apoptosis or necrosis. The protective effect against apoptosis or necrosis ensuing from the MPTT and PTT + PDT interventions was discernibly linked to the elevated expression of HSP27. Moreover, these interventions adeptly curbed intracellular cholesterol biosynthesis and excessive cholesterol uptake, facilitated through modulation of the SREBP2/LDLR pathway. Additionally, the interventions prompted ABCA1-mediated cholesterol efflux, culminating in the inhibition of lipid accumulation within foam cells.[146] This study’s outcomes impart novel insights into the underlying mechanism governing lipid regulation in foam cells. Furthermore, they underscore the potential of black TiO2nanoprobes to serve as a safer and more efficacious approach for phototherapy in the context of atherosclerosis. Liu et al. presented a photothermal nanocatalyst utilizing ferrous disulfide nanoplatform, designed specifically for catalytic drug therapy targeting epilepsy. Of significance is the enhancement of CDT efficacy through a NIR-II irradiation, which induces hyperthermia and synergistically combines the benefits of MPTT and CDT. In vivo investigations conducted on pentylenetetrazole kindling epileptic rats reveal a substantial reduction in both the frequency and severity of epileptic episodes after the ablation of the epileptogenic focus using this innovative approach.[147] This innovative strategy, which augments catalytic drug therapy with hyperthermia-based photothermal therapy, holds great potential as a novel therapeutic avenue for addressing focal epilepsy. Ma et al. developed a novel bifunctional nanoplatform consisting of Bi2_xMnxO3, which demonstrated a synergistic approach to tumor treatment through TME-triggered PTT and CDT. By incorporating a small amount of Bi dopant, the photothermal and CDT capabilities of Bi2_xMnxO3 were finely tuned, resulting in improved PCE and accelerated hydroxyl radical (•OH) generation. The introduction of reductive Mn4+ ions played a pivotal role in disturbing the internal redox balance of the tumor, leading to increased consumption of GSH and consequently enhancing the effectiveness of CDT. Simultaneously, the mild photothermal effect induced by the nanoplatform facilitated GSH depletion and •OH generation within the tumor region upon laser irradiation.[148] This dual action strategy further bolstered the CDT efficacy. Overall, this innovative manganese-based nanoplatform offers a promising avenue for tumor therapy by capitalizing on TME-mediated PTT-enhanced CDT. Yin et al. accomplished the successful synthesis of ultrasmall zirconium carbide (ZrC) nanodots, which exhibit remarkable properties including high near-infrared absorption and potent photon attenuation, thus enabling a synergistic approach involving MPTT and radiotherapy (RT) for glioma treatment. The ZrC–PVP nanodots, featuring an average diameter of approximately 4.36 nm, were fabricated through the liquid exfoliation method, and functionalized with the surfactant polyvinylpyrrolidone (PVP). These nanodots demonstrated impressive near-infrared absorption and PCE (53.4%), rendering them highly effective in NIR region. Notably, the ZrC–PVP nanodots exhibited the additional ability to function as radiosensitizers. This characteristic proved crucial in eliminating residual tumor cells post MPTT due to their exceptional photon attenuating capability.[149] This study systematically assessed the potential of ZrC–PVP nanodots for glioma treatment and supplied compelling evidence for the utility of zirconium-based nanomaterials in the realm of photothermal radiotherapy. Zhao et al. ingeniously crafted a virus-like nanoplatform termed SiOx/CeO2/VOx (SCV) for multifaceted therapeutic interventions, including 1064 nm NIR triggered MPTT and nanozyme catalytic therapy. The distinctive virus-like morphology of SCV was strategically designed to enhance cellular adhesion and uptake, thereby bolstering its internalization within cells. The SCV nanoplatform was adept at eliciting an effective PTT response upon exposure to 1064 nm laser irradiation. An intriguing aspect of this study was the role of the generated VO2+ species within TME. These species acted as inhibitors of HSP60 expression, thereby enhancing the efficacy of MPTT. Furthermore, the SCV nanoplatform exhibited remarkable peroxidase-mimicking (POD) catalytic activity, which manifested as the generation of highly cytotoxic •OH under acidic conditions. The combined effects of mild-temperature heating and •OH generation through enzymatic catalysis synergistically impeded tumor growth.[150] This synergistic outcome was robustly confirmed through meticulous in vitro and in vivo experiments. The innovative virus-like SCV nanoplatform, endowed with nanozyme activity akin to POD and a gentle photothermal influence, opens novel avenues for envisioning combination therapy paradigms.
3.2.3. Carbon-based nanomaterials
Carbon nanomaterials are a class of materials composed of nanoscale carbon elements with unique physical and chemical properties. The nanoscale size and high specific surface area give carbon nanomaterials excellent mechanical, optical, thermal, and electrical properties, as well as good biocompatibility and stability.[151, 152] Li et al. harnessed the unique properties of nanodiamonds (NDs) for use in MPTT as a means of treating cancer. To fully exploit the potential of combining multiple therapies in a single nanoplatform, the researchers adopted an innovative approach. They incorporated the hydrophobic anti-angiogenesis agent combretastatin A4 (CA4) into protamine sulfate (PS)-functionalized ND hybrids (NDs@PS) through a noncovalent self-assembly technique, resulting in CA4-NDs@PS nanodiamonds. This strategy aimed to achieve both anti-angiogenesis and MPTT simultaneously for liver cancer treatment.[153] Liu et al. developed a novel approach involving the inhibition of autophagy and lysosomal escape using PEG-PEI/CDs-E64d nanoagents. PEG was used as a carrier to combine PEI, which has a ”proton sponge” effect, with the autophagy inhibitor E64d. This approach aimed to enhance the sensitivity of tumor cells to treatment and improve the utilization of the photothermal agent, carbon QDs (CDs). The innovative combined strategy presented in this study represents a promising avenue for advancing the clinical application of MPTT.[154] Ning et al. developed an injectable ALG hydrogel consisting of several key components: a photothermal agent, Chinese ink; an azo initiator called AIPH; and a PD-L1 inhibitor, HY. Upon intratumoral injection, this hydrogel rapidly reacts with the calcium ions (Ca2+) within the tumor, forming an in-situ hydrogel to prevent premature release of the enclosed drugs. Upon NIR-II laser irradiation, the Chinese ink generates mild heat (maintained below 45 °C) to upregulate the expression of PD-L1 in tumor cells and releases damage-related molecular patterns (DAMPs). This transformation converted a ”cold” tumor into a ”hot” tumor. MPTT induced the rapid decomposition of AIPH, leading to the production of many alkyl radicals, and enhances ICD, thus potentiating immunotherapy.[155] In summary, this innovative approach offers a promising strategy for transforming cold tumors into hot tumors and enhancing the effectiveness of immunotherapy.
3.2.4. Other two-dimensional (2D) materials
Since the availability of mechanically stripped graphene in 2004, 2D nanomaterials have attracted increasing research interest. The ultra-thin thickness and relatively large transverse size of two-dimensional nanomaterials give them a variety of interesting properties, such as striking electronic properties, ultra-high specific surface area, excellent mechanical properties, etc.[156-158] Fu et al. introduced an innovative boron-based multifunctional nanoplatform designed for synergistic chemotherapy and MPTT. This platform was engineered with the addition of a cRGD peptide, facilitating the specific targeting of αvβ3 integrin, which is commonly overexpressed in tumor cells. The NPs were then loaded with the chemotherapeutic drug doxorubicin (DOX) and a HSP inhibitor (17AAG), which exhibited controlled release of DOX and 17AAG in response to changes in pH and NIR light exposure. Furthermore, it displayed significantly enhanced cellular uptake in cancerous cells compared to healthy cells. The inclusion of 17AAG allowed for the combination of MPTT with chemotherapy using DOX, leading to highly effective anticancer activity.[159] This efficacy was confirmed through both in vitro experiments and in vivo studies using a murine cancer model. In summary, this multifunctional nanoplatform holds promise as a valuable candidate for cancer therapy, offering a versatile approach for achieving synergistic treatment through targeted drug delivery and controlled release mechanisms. Tan et al. employed red phosphorus NPs to sensitize methicillin-resistant Staphylococcus aureus (MRSA) to conventional aminoglycoside antibiotics. They investigated the antibacterial mechanism using proteomic techniques and molecular dynamics (MD) simulations, confirming that MPTT selectively enhances the effectiveness of aminoglycoside antibiotics against MRSA. Their research revealed that the catalytic activity of 2-aminoglycoside phosphotransferase (APH (2″)), a modifying enzyme, is significantly inhibited. This inhibition was demonstrated by observing a decrease in ATP consumption during the catalytic reaction. Molecular dynamics simulations further showed that the active site containing aspartic acid (ASP) residues in APH (2″) becomes thermally unstable. This thermal instability hinders the deprotonation process required for gentamycin’s -OH group, thereby impairing APH (2″)’s catalytic ability.[160] Cao et al. introduced a novel approach involving copper sulfide/titanium oxide heterostructure nanosheets modified with hyaluronic acid (HA) and PEG (HA-HNSs) for the purpose of low-intensity sonodynamic therapy (SDT) and MPTT aimed at early atherosclerotic plaques. These CuS/TiO2heterostructure nanosheets (HNSs) are notable for their high electron-hole separation efficiency and exceptional sonodynamic performance, owing to their high surface energy crystal facets and a narrow bandgap. Furthermore, HNSs exhibit strong absorbance in the NIR-II region, which imparts excellent photothermal performance to the nanosheets. By further modifying these nanosheets with HA, HA-HNSs can selectively target proinflammatory macrophages within atherosclerotic plaques through the CD44-HA interaction. The combination of SDT, which reduces the expression of HSP90, and MPTT, which facilitated the sonocatalytic process, synergistically induces apoptosis in proinflammatory macrophages. Importantly, this synergistic therapy effectively hinders the progression of early atherosclerotic plaques by eliminating lesional macrophages and mitigating inflammation.[161] This study introduces a macrophage-targeting sonodynamic/photothermal synergistic therapy that holds promise as a clinically translational intervention for early-stage atherosclerotic plaques. Gao et al. introduced a novel nanostructure composed of transition metal dichalcogenides, specifically Bi2Se3/MoSe2 nanosaucers (BMNSs), designed to generate MPTT and combined with chemotherapy to enhance overall antitumor efficacy. The BMNSs consist of hexagonal Bi2Se3 nanoplates enclosed by MoSe2 nanosheets. The MoSe2 component contributes to excellent photothermal efficiency, while the Bi2Se3 substrates offer a large specific surface area for anchoring more DOX molecules, serving as the chemotherapeutic agent.[162] This study not only demonstrates a paradigm of achieving high therapeutic efficacy through mild hyperthermia and synergistic chemotherapy for precise cancer therapy but also highlights the potential for improving cancer treatment with minimal side effects through meticulous design of nanoplatform microstructures and physiochemical properties. Yang et al. developed a MPTT based on borneol-containing polymer-modified MXene nanosheets (BPM) with bacteria-targeting capabilities. BPM was fabricated through the electrostatic coassembly of negatively charged two-dimensional MXene nanosheets (2DM) and positively charged quaternized α-(+)-borneol-poly(N,N-dimethyl ethyl methacrylate) (BPQ) polymers. Integrating BPQ with 2DM improved the stability of 2DM in physiological environments and enabled the bacterial membrane to be targeted due to the presence of a borneol group and the partially positive charge of BPQ.[163] With the aid of NIR irradiation, BPM was able to effectively eliminate methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli) through targeted photothermal hyperthermia. More importantly, BPM effectively eradicated more than 99.999% (>5 orders of magnitude) of MRSA by localized heating at a temperature that is safe for the human body (≤40 °C). Together, these findings suggest that BPM has good biocompatibility and that membrane-targeting MPTT could have great therapeutic potential against MDR infections.