A NIR-II AIEgen-Based Supramolecular Nanodot for Peroxynitrite-Potentiated Mild-Temperature Photothermal Therapy of Hepatocellular Carcinoma

Compared to conventional photothermal therapy (PTT) which requires hyperthermia higher than 50 °C, mild-temperature PTT is a more promising antitumor strategy with much lower phototoxicity to neighboring normal tissues. However, the therapeutic efficacy of mild-temperature PTT is always restricted by the thermoresistance of cancer cells. To address this issue, a supramolecular drug nanocarrier is fabricated to co-deliver nitric oxide (NO) and photothermal agent DCTBT with NIR-II aggregation-induced emission (AIE) characteristic for mild-temperature PTT. NO can be effectively released from the nanocarriers in intracellular reductive environment and DCTBT is capable of simultaneously producing reactive oxygen species (ROS) and hyperthermia upon 808 nm laser irradiation. The generated ROS can further react with NO to produce peroxynitrite (ONOOˉ) bearing strong oxidization and nitration capability. ONOOˉ can inhibit the expression of heat shock proteins (HSP) to reduce the thermoresistance of cancer cells, which is necessary to achieve excellent therapeutic efficacy of DCTBT-based PTT at mild temperature (<50 °C). The antitumor performance of ONOOˉ-potentiated mild-temperature PTT is validated on subcutaneous and orthotopic hepatocellular carcinoma (HCC) models. This research puts forward an innovative strategy to overcome thermoresistance for mild-temperature PTT, which provides new inspirations to explore ONOOˉ-sensitized tumor therapy strategies.     

Nanoagent-Promoted Mild-Temperature Photothermal Therapy for Cancer Treatment

Photothermal therapy (PTT), which utilizes near-infrared light-absorbing agents to ablate tumor, has emerged as a highly promising anticancer strategy and received intensive clinical trials in recent years. Mild-temperature PTT, which circumvents the limitations of conventional PTT (e.g., thermoresistance and adverse effects), is emerging and shows great potential in the forthcoming clinical applications. However, mild-temperature PTT without adjuvant therapy is not able to completely eradicate tumors because its therapeutic efficacy is dramatically impaired by its inferior heat intensity. As a result, strategies capable of enhancing the anticancer efficacy of mild-temperature PTT are urgently necessitated, which mainly rely on on-demand fabrication of functionalized nanoagents. In this review, the strategies of nanoagent-promoted mild-temperature PTT are highlighted. Furthermore, challenges and opportunities in this field are rationally proposed, and hopefully people can be encouraged by this promising anticancer therapy.     

Self‐Mineralized Photothermal Bacteria Hybridizing with Mitochondria‐Targeted Metal–Organic Frameworks for Augmenting Photothermal Tumor Therapy

A photothermal bacterium (PTB) is reported for tumor‐targeted photothermal therapy (PTT) by using facultative anaerobic bacterium Shewanella oneidensis MR‐1 (S. oneidensis MR‐1) to biomineralize palladium nanoparticles (Pd NPs) on its surface without affecting bacterial activity. It is found that PTB possesses superior photothermal property in near infrared (NIR) regions, as well as preferential tumor‐targeting capacity. Zeolitic imidazole frameworks‐90 (ZIF‐90) encapsulating photosensitizer methylene blue (MB) are hybridized on the surface of living PTB to further enhance PTT efficacy. MB‐encapsulated ZIF‐90 (ZIF‐90/MB) can selectively release MB at mitochondria and cause mitochondrial dysfunction by producing singlet oxygen (¹O₂) under light illumination. Mitochondrial dysfunction further contributes to adenosine triphosphate (ATP) synthesis inhibition and heat shock proteins (HSPs) down‐regulated expression. The PTB‐based therapeutic platform of PTB@ZIF‐90/MB demonstrated here will find great potential to overcome the challenges of tumor targeting and tumor heat tolerance in PTT.     

Intracellular Bottom-up Synthesis of Ultrasmall CuS Nanodots in Cancer Cells for Simultaneous Photothermal Therapy and COX-2 Inactivation

The clinical application of photothermal therapy (PTT) is limited by the accuracy of thermal damage and the risk of tumor metastasis and relapse induced by hyperthermia-related inflammation. Intracellular bottom-up synthesis (iBuS) of CuS nanoparticles from small-molecule precursors inside tumor cells triggered by tumor specific stimuli is a promising strategy to enhance the precision of PTT treatment and reduce the risk of nondegradable metal nanoparticles. Herein, monolocking nanoparticles (MLNPs) with Cu-meloxicam complexes encapsulated by human serum albumin (HSA) are reported, which efficiently form CuS nanodots via the elevated concentration of endogenous H₂S inside tumor cells and meanwhile release meloxicam for anti-inflammatory effects. The intracellular bottom-up fabrication of CuS nanodots is directly visualized by TEM. An enhanced PTT effect is observed with 4T1 cells caused by additional meloxicam-induced inactivation of the COX-2 enzyme. After systemic administration, MLNPs completely ablate tumors under laser exposure, simultaneously inhibiting the inflammation induced by photothermal damage, and can be cleared via the kidney into urine. This strategy provides a new route for activated multimodal therapy, which could be applicable to precisely combat cancer.     

Immunotherapeutic Hydrogel with Photothermal Induced Immunogenic Cell Death and STING Activation for Post-Surgical Treatment

Post-surgical tumor recurrence remains a major clinical concern for patients with malignant solid tumors. Herein, an immunotherapeutic hydrogel (SA_PBA/ZMC/ICG) is developed by incorporating metal ion-cyclic dinucleotide (CDN) nanoparticles (Zn-Mn-CDN, ZMC) and a photosensitizer (indocyanine green, ICG) into phenylboronic acid (PBA)-conjugated sodium alginate (SA_PBA) for photothermal therapy (PTT)-triggered in situ vaccination to inhibit post-surgical recurrence and metastasis of malignant tumors. The gelation of SA_PBA/ZMC/ICG in the residual tumors can achieve accurate local PTT and the local sustained release of CDN and Mn²⁺ with minimal detrimental off-target toxic effects. Furthermore, CDN, which is an agonist of the stimulator of interferon genes (STING), along with Mn²⁺ can activate the STING pathway and trigger type-I-IFN-driven immune responses against tumors. Therefore, the immunotherapeutic hydrogel with enhanced immune response by STING agonist and PTT-induced immunogenic cell death (ICD) reprograms the post-surgical immunosuppressive microenvironment, substantially decreasing the post-surgical recurrence and metastasis of solid tumors in multiple murine tumor models when administered during surgical resection. Taken together, PTT-triggered and STING-mediated in situ cancer vaccination is an effective therapeutic intervention for post-surgical recurrence and metastasis of tumors.     

Human HSP70 Promoter‐Based Prussian Blue Nanotheranostics for Thermo‐Controlled Gene Therapy and Synergistic Photothermal Ablation

Realizing precise control of the therapeutic process is crucial for maximizing efficacy and minimizing side effects, especially for strategies involving gene therapy (GT). Herein, a multifunctional Prussian blue (PB) nanotheranostic platform is first designed and then loaded with therapeutic plasmid DNA (HSP70‐p53‐GFP) for near‐infrared (NIR) light‐triggered thermo‐controlled synergistic GT/photothermal therapy (PTT). Due to the unique structure of the PB nanocubes, the resulting PB@PEI/HSP70‐p53‐GFP nanoparticles (NPs) exhibit excellent photothermal properties and pronounced tumor‐contrast performance in T₁/T₂‐weighted magnetic resonance imaging. Both in vitro and in vivo studies demonstrate that mild NIR‐laser irradiation (≈41 °C) activates the HSP70 promoter for tumor suppressor p53‐dependent apoptosis, while strong NIR‐laser irradiation (≈50 °C) induces photothermal ablation for cellular dysregulation and necrosis. Significant synergistic efficacy can be achieved by adjusting the NIR‐laser irradiation (from ≈41 to ≈50 °C), compared to using GT or PTT alone. In addition, in vitro and in vivo toxicity studies demonstrate that PB@PEI/HSP70‐p53‐GFP NPs have good biocompatibility. Therefore, this work provides a promising theranostic approach for controlling combined GT and PTT via the heat‐shock response.     

One‐Pot Synthesis of Dual Stimulus‐Responsive Degradable Hollow Hybrid Nanoparticles for Image‐Guided Trimodal Therapy

Exploiting exogenous and endogenous stimulus‐responsive degradable nanoparticles as drug carriers can improve drug delivery systems (DDSs). The use of hollow nanoparticles may facilitate degradation, and combination of DDS with photodynamic therapy (PDT) and photothermal therapy (PTT) may enhance the anticancer effects of treatments. Here, a one‐pot synthetic method is presented for an anticancer drug (doxorubicin [DOX]) and photosensitizer‐containing hollow hybrid nanoparticles (HNPs) with a disulfide and siloxane framework formed in response to exogenous (light) and endogenous (intracellular glutathione [GSH]) stimuli. The hollow HNPs emit fluorescence within the near‐infrared window and allow for the detection of tumors in vivo by fluorescence imaging. Furthermore, the disulfides within the HNP framework are cleaved by intracellular GSH, deforming the HNPs. Light irradiation facilitates penetration of GSH into the HNP framework and leads to the collapse of the HNPs. As a result, DOX is released from the hollow HNPs. Additionally, the hollow HNPs generate singlet oxygen (¹O₂) and heat in response to light; thus, fluorescence imaging of tumors combined with trimodal therapy consisting of DDS, PDT, and PTT is feasible, resulting in superior therapeutic efficacy. Thus, this method may have several applications in imaging and therapeutics in the future.     

Enhanced Antitumor Efficacy by 808 nm Laser‐Induced Synergistic Photothermal and Photodynamic Therapy Based on a Indocyanine‐Green‐Attached W18O49 Nanostructure

A novel nanoplatform based on tungsten oxide (W₁₈O₄₉, WO) and indocyanine green (ICG) for dual‐modal photothermal therapy (PTT) and photodynamic therapy (PDT) has been successfully constructed. In this design, the hierarchical unique nanorod‐bundled W₁₈O₄₉ nanostructures play roles in being not only as an efficient photothermal agent for PTT but also as a potential nanovehicle for ICG molecules via electrostatic adsorption after modified with trimethylammonium groups on their surface. It is found that the ability of ICG to produce cytotoxic reactive oxygen species for PDT is well maintained after being attached on the WO, thus the as‐obtained WO@ICG can achieve a synergistic effect of combined PTT and PDT under single 808 nm near‐infrared (NIR) laser excitation. Notably, compared with PTT or PDT alone, the enhanced HeLa cells lethality of the 808 nm laser triggered dual‐modal therapy is observed. The in vivo animal experiments have shown that WO@ICG has effective solid tumor ablation effect with 808 nm NIR light irradiation, revealing the potential of these nanocomposites as a NIR‐mediated dual‐modal therapeutic platform for cancer treatment.     

Bacteria‐Assisted Selective Photothermal Therapy for Precise Tumor Inhibition

Photothermal therapy (PTT) has drawn extensive research attention as a promising approach for tumor treatment. In this study, a bacteria‐assisted strategy relying on the selective reduction of perylene diimide derivative based supramolecular complex (CPPDI) to radical anions (RAs) by Escherichia coli in hypoxic tumors is developed to realize highly precise PTT of tumors. Noninvasive E. coli are first injected intravenously for selectively accumulating and replicating in the tumor due to the hypoxia tropism. Then, CPPDI is loaded in a peptide‐hybrid matrix metalloproteinase‐2 (MMP‐2) responsive liposome (MRL) and injected intravenously. After accumulated and released from MRL in the tumor where MMP‐2 is overexpressed, CPPDI is reduced by E. coli in the hypoxic tumor environment to produce CPPDI RAs (CRAs), which serve as effective photothermal agents for tumor cells thermal ablation under near‐infrared light irradiation. Since E. coli accumulate and grow in tumor sites selectively, this strategy accurately limits the production of CRAs in tumors for highly selective PTT, which will find great potential for precise tumor inhibition.     

Effective Eradication of Tumors by Enhancing Photoacoustic-Imaging-Guided Combined Photothermal Therapy and Ultrasonic Therapy

Exploiting a comprehensive strategy that processes diagnosis and therapeutic functions is desired for eradicating tumors. In this study, two versatile nanoparticles are introduced: one is polyethylene glycol- and polyethyleneimine-modified gold nanorods (mPEG–PEI–AuNRs), and the other is formed by electrostatic interactions between mPEG–PEI and calcium carbonate nanoparticles (mPEG–PEI/CaNPs). These two nanoparticles possess following favorable properties: 1) mPEG–PEI–AuNRs and mPEG–PEI/CaNPs show not only high cell uptake in acidic tumoral pH, but also efficient accumulation in tumors with prolonged circulation. 2) mPEG–PEI/CaNPs can generate carbon dioxide (CO₂) bubbles in acidic tumoral environment and the photoacoustic (PA) signals from mPEG–PEI–AuNRs can be enhanced with the generation of CO₂ bubbles. 3) The tumors can be eradicated by combining photothermal therapy (PTT) with ultrasonic therapy (UST) under the near-infrared (NIR) laser and ultrasonic irradiation with the presence of mPEG–PEI–AuNRs and CO₂ bubbles from mPEG–PEI/CaNPs. The detailed evaluation of cellular uptake, photothermal property of mPEG–PEI–AuNRs, CO₂ bubbles’ generation from mPEG–PEI/CaNPs, imaging, and combined PTT and UST are carried out in vitro or in vivo. This work has great potential usage for diagnosis and treatment in the future.     

Unveiling the Multiple Tumor-Targeted Impairments of Covalent-Organic Framework-Switched Photothermal Shielding Nanoparticles

Covalent organic framework (COF) receives great attention in biomedical applications due to its variable compositions and ordered structures. However, its targeted design to achieve desirable physiological functions especially for cancer treatments remains elusive. Herein, PEGylated COF with tumor-specific TKD peptide modification is uniformly coated on photothermal mesoporous carbon nanospheres via polyethyleneimine-mediated interface polymerization to construct a multifunctional core-shell nanoparticle (OPCPT). Physicochemical studies demonstrate near infrared (NIR)-blocking ability of the crystalline COF shells under physiological conditions, whereas COF is degraded under the acidic tumor microenvironments (TME). Subsequently, the nanoparticle charge is reversed and the COF monomers can produce ¹O₂/O₂. As a result, OPCPT, activated in the TME due to the shell dissociation, penetrates deeply into tumors through positive charge-mediated/lysosome rupture-mediated transcytosis and recovers its NIR-heating potential for tumor-specific photothermal therapy. Moreover, the TME-triggered ¹O₂ significantly depresses the lysosome autophagy via membrane destruction, and selectively damages the mitochondria to promote the cytochrome C release-activated apoptosis and ATP deficiency-inhibited tumor metastasis. Particularly, this unique O₂ generation mechanism relieves the tumor hypoxia upon the reactive oxygen species therapy and downregulates hypoxia-inducible factor and its downstream proteins, which all contribute to augmented tumor therapy. The findings represent a remarkable unveiling of the potential of COF-based nanomaterials for extended biomedical applications.     

Designing Bioinspired 2D MoSe2 Nanosheet for Efficient Photothermal‐Triggered Cancer Immunotherapy with Reprogramming Tumor‐Associated Macrophages

Nonspecific absorption and clearance of nanomaterials during circulation is the major cause for treatment failure in nanomedicine‐based cancer therapy. Therefore, herein bioinspired red blood cell (RBC) membrane is employed to camouflage 2D MoSe₂ nanosheets with high photothermal conversion efficiency to achieve enhanced hemocompatibility and circulation time by preventing macrophage phagocytosis. RBC–MoSe₂‐potentiated photothermal therapy (PTT) demonstrates potent in vivo antitumor efficacy, which triggers the release of tumor‐associated antigens to activate cytotoxic T lymphocytes and inactivate the PD‐1/PD‐L1 pathway to avoid immunologic escape. Furthermore, in the ablated tumor microenvironment, the tumor‐associated macrophages are effectively reprogrammed to tumoricidal M1 phenotype to potentiate the antitumor action. Taken together, this biomimetic functionalization thus provides a substantial advance in personalized PTT‐triggered immunotherapy for clinical translation.     

Robust Nanovaccine Based on Polydopamine-Coated Mesoporous Silica Nanoparticles for Effective Photothermal-Immunotherapy Against Melanoma

Nanoparticle-based combination therapy strategy of photothermal therapy (PTT) and immunotherapy is an attractive cancer treatment for ablating tumors and eliciting host immune responses. However, this strategy is often hampered by tedious treatment process and limited immune response, and usually needs to be combined with checkpoint blockades to enhance therapeutic effect. Herein, a nanoplatform with mesoporous silica nanoparticles (MSNs) as a vector, which integrated photothermal agent polydopamine (PDA), model antigen ovalbumin (OVA), and antigen release promoter ammonium bicarbonate (ABC) in an easy way for melanoma PTT-immunotherapy is designed. The formulated MSNs-ABC@PDA-OVA nanovaccine exhibits excellent photothermal properties and effectively eliminates primary tumors. Under laser irradiation, the MSNs-ABC@PDA-OVA nanovaccine realizes rapid antigen release and endosome escape, enhances dendritic cells activation and maturation, facilitates migration to tumor-draining lymph nodes, and induces robust antitumor immune responses. Impressively, single injection of MSNs-ABC@PDA-OVA combines with single round of PTT successfully eradicates melanoma tumors with a cure rate of 75% and generates strong immunological memory to inhibit tumor recurrence and lung metastasis. Hence, the research offers a simple and promising strategy of synergistic PTT-immunotherapy to effectively treat cancer.     

Design and Synthesis of “All‐in‐One” Multifunctional FeS2 Nanoparticles for Magnetic Resonance and Near‐Infrared Imaging Guided Photothermal Therapy of Tumors

The ideal theranostic nanoplatform for tumors is a single nanoparticle that has a single semiconductor or metal component and contains all multimodel imaging and therapy abilities. The design and preparation of such a nanoparticle remains a serious challenge. Here, with FeS₂ as a model of a semiconductor, the tuning of vacancy concentrations for obtaining “all‐in‐one” type FeS₂ nanoparticles is reported. FeS₂ nanoparticles with size of ≈30 nm have decreased photoabsorption intensity from the visible to near‐infrared (NIR) region, due to a low S vacancy concentration. By tuning their shape/size and then enhancing the S vacancy concentration, the photoabsorption intensity of FeS₂ nanoparticles with size of ≈350 nm (FeS₂‐350) goes up with the increase of the wavelength from 550 to 950 nm, conferring the high NIR photothermal effect for thermal imaging. Furthermore, this nanoparticle has excellent magnetic properties for T₂‐weighted magnetic resonance imaging (MRI). Subsequently, FeS₂‐350 phosphate buffer saline (PBS) dispersion is injected into the tumor‐bearing mice. Under the irradiation of 915‐nm laser, the tumor can be ablated and the metastasis lesions in liver suffer significant inhibition. Therefore, FeS₂‐350 has great potential to be used as novel “all‐in‐one” multifunctional theranostic nanoagents for MRI and NIR dual‐modal imaging guided NIR‐photothermal ablation therapy (PAT) of tumors.     

Thermoresponsive Nanogel‐Encapsulated PEDOT and HSP70 Inhibitor for Improving the Depth of the Photothermal Therapeutic Effect

Photothermal therapy (PTT), a new, noninvasive treatment measure, has recently drawn much attention. However, due to the limited penetration depth of near‐infrared (NIR) light, PTT is focused on treating superficial tumors. Improving the depth of the therapeutic effect is a bottleneck for successful PTT. To solve this problem, a new kind of nanoplatform (Nanogel+phenylethynesulfonamide (PES)) is fabricated by using a thermo‐responsive polymer shell (poly(N‐isopropylacrylamide‐co‐acrylic acid) to encapsulate 2‐PES, an effective heat shock protein 70 (HSP70) inhibitor, and poly(3,4‐ethylenedioxythiophene), a widely used photothermal coupling agent. Upon NIR irradiation, PES can be released from the Nanogel+PES when a thermo‐responsive phase transition occurs, which could restrain the function of HSP70 and reduces the cells' endurance to heat. In this way, a better therapeutic effect on deeper tissues is achieved with a relatively small rise in temperature. Therefore, with the advantages of the thermo‐responsive photothermal effect, coupled with the inhibition of HSP70, and minimal cytotoxicity, the Nanogel+PES appears to be a promising photothermal agent that can improve the depth of the PTT effect.     

Hollow Nanostars with Photothermal Gold Caps and Their Controlled Surface Functionalization for Complementary Therapies

Gold nanoparticles exhibiting absorption in the desirable near‐infrared region are attractive candidates for photothermal therapy (PTT). Furthermore, the construction of one nanoplatform employing gold nanoparticles for complementary therapy is still a great challenge. Here, well‐defined unique hollow silica nanostars with encapsulated gold caps (starlike Au@SiO₂) are readily synthesized using a sacrificial template method. Ethanolamine‐functionalized poly(glycidyl methacrylate) (denoted as BUCT‐PGEA) brushes are then grafted controllably from the surface of starlike Au@SiO₂ nanoparticles via surface‐initiated atom transfer radical polymerization to produce starlike Au@SiO₂‐PGEA. The photothermal effect of gold caps with a cross cavity can be utilized for PTT. The interior hollow feature of starlike Au@SiO₂ nanoparticles endows them with excellent drug loading capability for chemotherapy, while the polycationic BUCT‐PGEA brushes on the surface provide good transfection performances for gene therapy, which will overcome the penetration depth limitation of PTT for tumor therapy. Compared with ordinary spherical Au@SiO₂‐PGEA counterparts, the starlike Au@SiO₂‐PGEA hybrids with sharp horns favor endocytosis, which can contribute to enhanced antitumor effectiveness. The rational integration of photothermal gold caps, hollow nanostars, and polycations through the facile strategy might offer a promising avenue for complementary cancer therapy.     

Magnetic (Hyper)Thermia or Photothermia? Progressive Comparison of Iron Oxide and Gold Nanoparticles Heating in Water,in Cells,and In Vivo

Magnetic hyperthermia (MHT) and photothermal therapy (PTT) are emergent state‐of‐the‐art modalities for thermal treatment of cancer. While their mechanisms of action have distinct physical bases, both approaches rely on nanoparticle‐mediated remote onset of thermotherapy. Yet, are the two heating techniques interchangeable? Here, the heating obtained either with MHT or with PTT is compared. The heating is assessed in distinct environments and involves a set of nanomaterials differing in shape (spheres, cubes, stars, shells, and rods) as well as in composition (maghemite, magnetite, cobalt ferrite, and gold). The nanoparticle's heating efficacy in an aqueous medium is first evaluated. Subsequently, the heating efficiency within the cellular environment, where intracellular processing markedly decreases MHT, is compared. Conversely, endosomal sequestration could have a positive effect on PTT. Finally, iron oxide nanocubes and gold nanostars are compared in MHT and PTT in vivo within the heterogeneous intratumoral environment. Overall, two distinct therapeutic approaches, related to high dosage allowing MHT and low dosage associated with PTT, are identified. It is also demonstrated that PTT mediated by magnetic nanoparticles has an efficacy that is comparable to that of plasmonic nanoparticles, but only at significant nanoparticle dosages. At low concentrations, only plasmonic nanoparticles can deliver a therapeutic heating.     

An Acceptor–Donor–Acceptor Structured Small Molecule for Effective NIR Triggered Dual Phototherapy of Cancer

Dual phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is regarded as a more effective method for cancer treatment than single PDT or PTT. However, development of single component and near‐infrared (NIR) triggered agents for efficient dual phototherapy remains a challenge. Herein, a simple strategy to develop dual‐functional small‐molecules‐based photosensitizers for combined PDT and PTT treatment is proposed through: 1) finely modulating HOMO–LUMO energy levels to regulate the intersystem crossing (ISC) process for effective singlet oxygen (¹O₂) generation for PDT; 2) effectively inhibiting fluorescence via strong intramolecular charge transfer (ICT) to maximize the conversion of photo energy to heat for PTT or ISC process for PDT. An acceptor–donor–acceptor (A‐D‐A) structured small molecule (CPDT) is designed and synthesized. The biocompatible nanoparticles, FA‐CNPs, prepared by encapsulating CPDT directly with a folate functionalized amphipathic copolymer, present strong NIR absorption, robust photostability, cancer cell targeting, high photothermal conversion efficiency as well as efficient ¹O₂ generation under single 808 nm laser irradiation. Furthermore, synergistic PDT and PTT effects of FA‐CNPs in vivo are demonstrated by significant inhibition of tumor growth. The proposed strategy may provide a new approach to reasonably design and develop safe and efficient photosensitizers for dual phototherapy against cancer.     

An Ultrasmall SnFe2O4 Nanozyme with Endogenous Oxygen Generation and Glutathione Depletion for Synergistic Cancer Therapy

The tumor microenvironment (TME) with the characteristics of severe hypoxia, overexpressed glutathione (GSH), and high levels of hydrogen peroxide (H₂O₂) dramatically limits the antitumor efficiency by monotherapy. Herein, a novel TME-modulated nanozyme employing tin ferrite (SnFe₂O₄, abbreviated as SFO) is presented for simultaneous photothermal therapy (PTT), photodynamic therapy (PDT), and chemodynamic therapy (CDT). The as-fabricated SFO nanozyme demonstrates both catalase-like and GSH peroxidase-like activities. In the TME, the activation of H₂O₂ leads to the generation of hydroxyl radicals (•OH) in situ for CDT and the consumption of GSH to relieve antioxidant capability of the tumors. Meanwhile, the nanozyme can catalyze H₂O₂ to generate oxygen to meliorate the tumor hypoxia, which is beneficial to achieve better PDT. Furthermore, the SFO nanozyme irradiated with 808 nm laser displays a prominent phototherapeutic effect on account of the enhanced photothermal conversion efficiency (η  = 42.3%) and highly toxic free radical production performance. This “all in one” nanozyme integrated with multiple treatment modalities, computed tomography, and magnetic resonance imaging properties, and persistent modulation of TME exhibits excellent tumor theranostic performance. This strategy may provide a new dimension for the design of other TME-based anticancer strategies.     

In Situ Nanozyme-Amplified NIR-II Phototheranostics for Tumor-Specific Imaging and Therapy

The discovery of near-IR-II (NIR-II) tumor phototheranostics holds a great promise for use in nanomedicine on account of its enhanced penetration depth, high spatial resolution, and noninvasiveness. However, contemporary “always on” phototherapeutic agents often have many undesirable side effects that hinder their clinical trial progress. To overcome this dilemma, an in situ nanozyme-amplified chromogenic nanoreactor by loading 3,3′,5,5′-tetramethylbenzidine (TMB) and ultrasmall PtAu nanoparticles into a metal–organic framework is developed for specific tumor theranostics, leaving normal tissues unharmed. As an intelligent photoacoustic diagnostic agent, the as-constructed nanoreactor remains silent until they enter the tumor site (H₂O₂-activated and acid-enhanced conditions) and turns on the photoacoustic signal to render a preoperative tumor diagnosis. As a nanozyme, the special microenvironment of the tumor tissue is used to initiate its catalytic damage by reactive oxygen species for chemodynamic therapy (CDT). More importantly, the TMB is oxidized, and the subsequent photothermal therapy (PTT) can be realized, leading to an optimal combination of CDT and PTT to concurrently fight obstinate cancers. The present “all-in-one” phototheranostics utilize nanozyme-augmented NIR-II agents for specific tumor ablation, which are promising for further development of intelligent nanozymes in tumor therapy.