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.