Photostable Iodinated Silica/Porphyrin Hybrid Nanoparticles with Heavy‐Atom Effect for Wide‐Field Photodynamic/Photothermal Therapy Using Single Light Source

Physical therapies including photodynamic therapy (PDT) and photothermal therapy (PTT) can be effective against diseases that are resistant to chemotherapy and remain as incurable malignancies (for example, multiple myeloma). In this study, to enhance the treatment efficacy for multiple myeloma using the synergetic effect brought about by combining PDT and PTT, iodinated silica/porphyrin hybrid nanoparticles (ISP HNPs) with high photostability are developed. They can generate both ¹O₂ and heat with irradiation from a light‐emitting diode (LED), acting as photosensitizers for PDT/PTT combination treatment. ISP HNPs exhibit the external heavy atom effect, which significantly improves both the quantum yield for ¹O₂ generation and the light‐to‐heat conversion efficiency. The in vivo fluorescence imaging demonstrates that ISP HNPs, modified with folic acid and polyethylene glycol (FA‐PEG‐ISP HNPs), locally accumulate in the tumor after 18 h of their intravenous injection into tumor‐bearing mice. The LED irradiation on the tumor area of the mice injected with FA‐PEG‐ISP HNPs causes necrosis of the tumor tissues, resulting in the inhibition of tumor growth and an improvement in the survival rate.     

High‐Security Nanocluster for Switching Photodynamic Combining Photothermal and Acid‐Induced Drug Compliance Therapy Guided by Multimodal Active‐Targeting Imaging

High‐security nanoplatform with enhanced therapy compliance is extremely promising for tumor. Herein, using a simple and high‐efficient self‐assembly method, a novel active‐targeting nanocluster probe, namely, Ag₂S/chlorin e6 (Ce6)/DOX@DSPE‐mPEG₂₀₀₀‐folate (ACD‐FA) is synthesized. Experiments indicate that ACD‐FA is capable of specifically labeling tumor and guiding targeting ablation of the tumor via precise positioning from fluorescence and photoacoustic imaging. Importantly, the probe is endowed with a photodynamic “on‐off” effect, that is, Ag₂S could effectively quench the fluorescence of chlorin e6 (89.5%) and inhibit release of ¹O₂ (92.7%), which is conducive to avoid unwanted phototoxicity during transhipment in the body, and only after nanocluster endocytosed by tumor cells could release Ce6 to produce ¹O₂. Moreover, ACD‐FA also achieves excellent acid‐responsive drug release, and exhibits eminent chemo‐photothermal and photodynamic effects upon laser irradiation. Compared with single or two treatment combining modalities, ACD‐FA could provide the best cancer therapeutic effect with a relatively low dose, because it made the most of combined effect from chemo‐photothermal and controlled photodynamic therapy, and significantly improves the drug compliance. Besides, the active‐targeting nanocluster notably reduces nonspecific toxicity of both doxorubicin and chlorin e6. Together, this study demonstrates the potency of a newly designed nanocluster for nonradioactive concomitant therapy with precise tumor‐targeting capability.     

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.     

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.     

Enzyme‐Mediated Tumor Starvation and Phototherapy Enhance Mild‐Temperature Photothermal Therapy

Compared with conventional tumor photothermal therapy (PTT), mild‐temperature PTT brings less damage to normal tissues, but also tumor thermoresistance, introduced by the overexpressed heat shock protein (HSP). A high dose of HSP inhibitor during mild‐temperature PTT might lead to toxic side effects. Glucose oxidase (GOx) consumes glucose, leading to adenosine triphosphate supply restriction and consequent HSP inhibition. Therefore, a combinational use of an HSP inhibitor and GOx not only enhances mild‐temperature PTT but also minimizes the toxicity of the inhibitor. However, a GOx and HSP inhibitor‐encapsulating nanostructure, designed for enhancing its mild‐temperature tumor PTT efficiency, has not been reported. Thermosensitive GOx/indocyanine green/gambogic acid (GA) liposomes (GOIGLs) are reported to enhance the efficiency of mild‐temperature PTT of tumors via synergistic inhibition of tumor HSP by the released GA and GOx, together with another enzyme‐enhanced phototherapy effect. In vitro and in vivo results indicate that this strategy of tumor starvation and phototherapy significantly enhances mild‐temperature tumor PTT efficiency. This strategy could inspire people to design more delicate platforms combining mild‐temperature PTT with other therapeutic methods for more efficient cancer treatment.     

A Versatile Prodrug Strategy to In Situ Encapsulate Drugs in MOF Nanocarriers: A Case of Cytarabine‐IR820 Prodrug Encapsulated ZIF‐8 toward Chemo‐Photothermal Therapy

Zeolitic imidazolate framework‐8 (ZIF‐8) is an attractive metal organic framework (MOF) in drug delivery. Strong interaction between drugs and ZIF‐8 is essential for high drug loadings through in situ construction of MOFs. However, only limited drugs with unique functional groups (? COOH, ? SO₃H, et al.) can interact with ZIF‐8 and be encapsulated satisfactorily so far. Drugs without these functional groups are difficult to be loaded due to the lack of strong interaction. Herein a versatile prodrug strategy is proposed to solve the problems encountered by MOFs. Cytarabine (Ara) is chosen as a model drug since it cannot be loaded in ZIF‐8 satisfactorily by itself. New indocyanine green (IR820) is utilized to bond with Ara for the formation of prodrug (Ara‐IR820) and endows the prodrug with fluorescence imaging‐guided chemo‐photothermal therapy, in which sulfonic groups strengthen the interaction between prodrug and ZIF‐8. This prodrug loaded ZIF‐8 is further functionalized with hyaluronic acid (HA) to result in active‐targeting HA/Ara‐IR820@ZIF‐8 nanoparticles. The in vitro and in vivo results demonstrate its excellent visual cancer therapy with tumor‐targeted and pH‐responsive release behavior. This design offers a new concept to solve the drug loading problem of MOFs, exhibiting a flexible strategy to expand the biomedical applications of MOFs.     

Increasing Photothermal Efficacy by Simultaneous Intra‐ and Intermolecular Fluorescence Quenching

Recently, using in situ self‐assembly‐induced fluorescence quenching (i.e., intermolecular quenching denoted herein) of a photothermal agent (PTA) to enhance its photothermal efficiency has proven to be a successful photothermal therapy (PTT) strategy. But to the best of current knowledge, using simultaneous intra‐ and intermolecular fluorescence quenching of a PTA to additionally increase its photothermal efficacy has not been reported. Herein, employing a click condensation reaction and a rationally designed PTA Biotin‐Cystamine‐Cys‐Lys(Cypate)‐CBT ( 1 ), a “smart” strategy is developed of intracellular simultaneous intra‐ and intermolecular fluorescence quenching and applied it to largely increase the photothermal efficacy of the agent both in vitro and in vivo. After being internalized by biotin receptor‐overexpressing cancer cells, 1 is reduced by intracellular glutathione to initiate a CBT‐Cys condensation reaction (intramolecular quenching) and self‐assembly (intermolecular quenching) to form the nanoparticles 1‐NPs (simultaneous intra‐ and intermolecular fluorescence quenching). Experimental results indicate that 1‐NPs have higher fluorescence quenching efficiency than the control PTAs [Thiazole‐Lys(Cypate)‐Benzothiazole]₂ ( 1‐Dimer , intramolecular quenching), and nanoparticles of Cystamine‐Cys(Fmoc)‐Lys(Cypate)‐CBT ( 1‐Fmoc‐NPs , intermolecular quenching). It is envisioned that, by replacing the biotin group on 1 with other targeting warheads, the “smart” strategy is ready to increase the photothermal therapeutic efficiency of their corresponding diseases.     

Combination of Bacterial‐Photothermal Therapy with an Anti‐PD‐1 Peptide Depot for Enhanced Immunity against Advanced Cancer

Photothermal therapy (PTT) is a promising cancer treatment, but it has so far proven successful only with relatively small subcutaneous tumors in animal models. Treating larger tumors (≈200 mm³) is challenging because most PTT materials do not efficiently reach the hypoxic, avascular center of tumors, and the immunosuppressive tumor microenvironment prevents T cells from fighting against residual tumor cells, thereby allowing recurrence and metastasis. Here, the widely used PTT material polydopamine is coated on the surface of the facultative anaerobe Salmonella VNP20009, which can penetrate deep into larger tumors. The coated bacteria are intravenously injected followed by near‐infrared laser irradiation at the tumor site, combined with a local inoculation of phospholipid‐based phase separation gel containing the anti‐programmed cell death‐1 peptide AUNP‐12. The gel releases AUNP‐12 sustainably during 42 days, maintaining the tumor microenvironment as immunopermissive. Using a mouse model of melanoma, this triple combination of biotherapy, PTT, and sustainable programmed cell death‐1 (PD‐1) blockade shows high efficiency on eliciting robust antitumor immune responses and eliminating relatively large tumors in 50% of animals within 80 days. Thus, the results shed new light on a previously unrecognized immunological facet of bacteria‐mediated therapy, and this innovative triple therapy may be a powerful cancer immunotherapy tool.     

Photoacoustic Imaging Guided Near‐Infrared Photothermal Therapy Using Highly Water‐Dispersible Single‐Walled Carbon Nanohorns as Theranostic Agents

The poly(maleic anhydride‐alt‐1‐octadecene‐poly(ethylene glycol)) (C₁₈PMH‐PEG) modified single‐walled carbon nanohorns (SWNHs) are designed with high stability and biocompatibility. The as‐prepared SWNHs/C₁₈PMH‐PEG not only can serve as an excellent photothermal agent but also can be used as a promising photoacoustic imaging (PAI) agent both in vitro and in vivo due to its strong absorption in the near infrared (NIR) region. The PAI result reveals that the SWNHs/C₁₈PMH‐PEG possesses ultra long blood circulation time and can significantly be accumulated at the tumor site through the enhanced penetration and retention (EPR) effect. The maximum accumulation of SWNHs/C₁₈PMH‐PEG at tumor site could be achieved at the time point of 24 h after intravenous injection, which is considered to be the optimal time for the 808 nm laser treatment. The subsequent photothermal ablation of tumors can be achieved without triggering any side effects. Therefore, a PAI guided PTT platform based on SWNHs is proposed and highlights the potential theranostic application for biomedical uses.     

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.     

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.     

Ultrasmall Semiconducting Polymer Dots with Rapid Clearance for Second Near‐Infrared Photoacoustic Imaging and Photothermal Cancer Therapy

Phototheranostic agents in the second near‐infrared (NIR‐II) window (1000–1700 nm) are emerging as a promising theranostic platform for precision medicine due to enhanced penetration depth and minimized tissue exposure. The development of metabolizable NIR‐II nanoagents for imaging‐guided therapy are essential for noninvasive disease diagnosis and precise ablation of tumors. Herein, metabolizable highly absorbing NIR‐II conjugated polymer dots (Pdots) are reported for the first time for photoacoustic imaging guided photothermal therapy (PTT). The unique design of low‐bandgap D‐A π‐conjugated polymer (DPP‐BTzTD) together with modified nanoreprecipitation conditions allows to fabricate NIR‐II absorbing Pdots with ultrasmall (4 nm) particle size. Extensive experimental tests demonstrate that the constructed Pdots exhibit good biocompatibility, excellent photostability, bright photoacoustic signals, and high photothermal conversion efficiency (53%). In addition, upon tail‐vein intravenous injection of tumor‐bearing mice, Pdots also show high‐efficient tumor ablation capability with rapid excretion from the body. In particular, both in vitro and in vivo assays indicate that the Pdots possess remarkable PTT performance under irradiation with a 1064 nm laser with 0.5 W cm^?2, which is much lower than its maximum permissible exposure limit of 1 W cm^?2. This pilot study thus paves a novel avenue for the development of organic semiconducting nanoagents for future clinical translation.     

Long‐Circulating Drug‐Dye‐Based Micelles with Ultrahigh pH‐Sensitivity for Deep Tumor Penetration and Superior Chemo‐Photothermal Therapy

Nanocarriers for chemo‐photothermal therapy suffer from insufficient retention at the tumor site and poor penetration into tumor parenchyma. A smart drug‐dye‐based micelle is designed by making the best of the structural features of small‐molecule drugs. P‐DOX is synthesized by conjugating doxorubicin (DOX) with poly(4‐formylphenyl methacrylate‐co‐2‐(diethylamino) ethyl methacrylate)‐b‐polyoligoethyleneglycol methacrylate (P(FPMA‐co‐DEA)‐b‐POEGMA) via imine linkage. Through the π–π stacking interaction, IR780, a near‐infrared fluorescence dye as well as a photothermal agent, is integrated into the micelles (IR780‐PDMs) with the P‐DOX. The IR780‐PDMs show remarkably long blood circulation (t_1/2β = 22.6 h). As a result, a progressive tumor accumulation and retention are presented, which is significant to the sequential drug release. Moreover, when entering into a moderate acidic tumor microenvironment, IR780‐PDMs can dissociate into small‐size conjugates and IR780, which obviously increases the penetration depth of drugs, and then improves the lethality to deep‐seated tumor cells. Owing to the high delivery efficiency and superior chemo‐photothermal therapeutic efficacy of IR780‐PDMs, 97.6% tumor growth in the A549 tumor‐bearing mice is suppressed with a low dose of intravenous injection (DOX, 1.5 mg kg^?1; IR780, 0.8 mg kg^?1). This work presents a brand‐new strategy for long‐acting intensive cancer therapy.     

pH‐Responsive Cyanine‐Grafted Graphene Oxide for Fluorescence Resonance Energy Transfer‐Enhanced Photothermal Therapy

Stimuli‐responsive anticancer agents are of particular interest in the field of cancer therapy. Nevertheless, so far stimuli‐responsive photothermal agents have been explored with limited success for cancer photothermal therapy (PTT). In this work, as a proof‐of‐concept, a pH‐responsive photothermal nanoconjugate for enhanced PTT efficacy, in which graphene oxide (GO) with broad NIR absorbance and effective photothermal conversion efficiency is selected as a typical model receptor of fluorescence resonance energy transfer (FRET), and grafted cyanine dye (e.g., Cypate) acts as the donor of near‐infrared fluorescence (NIRF), is reported for the first time. The conjugate of Cypate‐grafted GO exhibits different conformations in aqueous solutions at various pH, which can trigger pH‐dependent FRET effect between GO and Cypate and thus induce pH‐responsive photothermal effect of GO‐Cypate. GO‐Cypate exhibits severe cell damage owing to the enhanced photothermal effect in lysosomes, and thus generate synergistic PTT efficacy with tumor ablation upon photoirradiation after a single‐dose intravenous injection. The photothermal nanoconjugate with broad NIR absorbance as the effective receptor of FRET can smartly convert emitted NIRF energy from donor cyanine dye into additional photothermal effect for improving PTT. These results suggest that the smart nanoconjugate can act as a promising stimuli‐responsive photothermal nanoplatform for cancer therapy.     

Ultrasmall CuCo2S4 Nanocrystals: All‐in‐One Theragnosis Nanoplatform with Magnetic Resonance/Near‐Infrared Imaging for Efficiently Photothermal Therapy of Tumors

Copper‐based ternary bimetal chalcogenides have very promising potential as multifunctional theragnosis nanoplatform for photothermal treatment of tumors. However, the design and synthesis of such an effective platform remains challenging. In this study, hydrophilic CuCo₂S₄ nanocrystals (NCs) with a desirable size of ≈10 nm are synthesized by a simple one‐pot hydrothermal route. The as‐prepared ultrasmall CuCo₂S₄ NCs show: 1) intense near‐infrared absorption, which is attributed to 3d electronic transitions from the valence band to an intermediate band, as identified by density functional theory calculations; 2) high photothermal performance with a photothermal conversion efficiency up to 73.4%; and 3) capability for magnetic resonance (MR) imaging, as a result of the unpaired 3d electrons of cobalt. Finally, it is demonstrated that the CuCo₂S₄ NCs are a promising “all‐in‐one” photothermal theragnosis nanoplatform for photothermal cancer therapy under the irradiation of a 915 nm laser at a safe power density of 0.5 W cm^?2, guided by MR and infrared thermal imaging. This work further promotes the potential applications of ternary bimetal chalcogenides for photothermal theragnosis therapy.     

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.     

PEGylated Polypyrrole Nanoparticles Conjugating Gadolinium Chelates for Dual‐Modal MRI/Photoacoustic Imaging Guided Photothermal Therapy of Cancer

Polypyrrole nanoparticles conjugating gadolinium chelates were successfully fabricated for dual‐modal magnetic resonance imaging (MRI) and photoacoustic imaging guided photothermal therapy of cancer, from a mixture of pyrrole and pyrrole‐1‐propanoic acid through a facile one‐step aqueous dispersion polymerization, followed by covalent attachment of gadolinium chelate, using polyethylene glycol as a linker. The obtained PEGylated poly­pyrrole nanoparticles conjugating gadolinium chelates (Gd‐PEG‐PPy NPs), sized around around 70 nm, exhibited a high T₁ relaxivity coefficient of 10.61 L mm ^?1 s^?1, more than twice as high as that of the relating free Gd³⁺ complex (4.2 L mm ^–1 s^?1). After 24 h intravenous injection of Gd‐PEG‐PPy NPs, the tumor sites exhibited obvious enhancement in both T₁‐weighted MRI intensity and photoacoustic signal compared with that before injection, indicating the efficient accumulation of Gd‐PEG‐PPy NPs due to the introduction of the PEG layer onto the particle surface. In addition, tumor growth could be effectively inhibited after treatment with Gd‐PEG‐PPy NPs in combination with near‐infrared laser irradiation. The passive targeting and high MRI/photo­acoustic contrast capability of Gd‐PEG‐PPy NPs are quite favorable for precise cancer diagnosing and locating the tumor site to guide the external laser irradiation for photothermal ablation of tumors without damaging the surrounding healthy tissues. Therefore, Gd‐PEG‐PPy NPs may assist in better monitoring the therapeutic process, and contribute to developing more effective “personalized medicine,” showing great potential for cancer diagnosis and therapy.     

Mutually Synergistic Nanoparticles for Effective Thermo‐Molecularly Targeted Therapy

Photothermal therapy (PTT) is of particular importance as a highly potent therapeutic modality in cancer therapy. However, a critical challenge still remains in the exploration of highly effective strategy to maximize the PTT efficiency due to tumor thermoresistance and thus frequent tumor recurrence. Here, a rational fabrication of the micelles that can achieve mutual synergy of PTT and molecularly targeted therapy (MTT) for tumor ablation is reported. The micelles generate both distinct photothermal effect from Cypate through enhanced photothermal conversion efficiency and pH‐dependent drug release. The micelles further exhibit effective cytoplasmic translocation of 17‐allylamino‐17‐demethoxygeldanamycin (17AAG) through reactive oxygen species mediated lysosomal disruption caused by Cypate under irradiation. Translocated 17AAG specifically bind with heat shock protein 90 (HSP90), thereby inhibiting antiapoptotic p‐ERK1/2 proteins for producing preferable MTT efficiency through early apoptosis. Meanwhile, translocated 17AAG molecules further block stressfully overexpressed HSP90 under irradiation and thus inhibit the overexpression of p‐Akt for achieving the reduced thermoresistance of tumor cells, thus promoting the PTT efficiency through boosting both early and late apoptosis of Cypate. Moreover, the micelles possess enhanced resistance to photobleaching, preferable cellular uptake, and effective tumor accumulation, thus facilitating mutually synergistic PTT/MTT treatments with tumor ablation. These findings represent a general approach for potent cancer therapy.     

Size Switchable Nanoclusters Fueled by Extracellular ATP for Promoting Deep Penetration and MRI‐Guided Tumor Photothermal Therapy

Protein‐based theranostic agents (PBTAs) exhibit superior performance in the diagnosis and therapy of cancers. However, the in vivo applications of PBTA are largely limited by undesired accumulation, penetration, or selectivity. Here, an ATP‐supersensitive protein cluster is fabricated for promoting PBTA delivery and enhancing magnetic resonance imaging (MRI)‐guided tumor photothermal therapy. Gd³⁺‐ and CuS‐coloaded small bovine serum albumin nanoparticles (GdCuB) are synthesized as the model protein with a size of 9 nm and are encapsulated into charge switchable polycations (DEP) to form DEP/GdCuB nanoclusters of 120 nm. In blood circulation, DEP/GdCuB significantly extends the half‐lifetime and thereby enhances the tumor accumulation of GdCuB. When the clusters reach the tumor site, the extracellular adenosine triphosphate (ATP) can effectively trigger the release of GdCuB, resulting in tumoral deep penetration as well as the activation of T₁‐weighted MRI (r₁ value switched from 2.8 × 10^?3 to 11.8 × 10^?3 m ^?1 s^?1). Furthermore, this delivery strategy also improves the tumoral photothermal therapy efficacy with the MRI‐guided therapy. The study of ATP‐activated nanoclusters develops a novel strategy for tumor deep penetration and on/off imaging of PBTA by size switchable technology, and reveals the potential for MRI‐guided therapy of cancers.     

NIR Light‐Triggered Degradable MoTe2 Nanosheets for Combined Photothermal and Chemotherapy of Cancer

Telluride molybdenum (MoTe₂) nanosheets with wide near‐infrared (NIR) absorbance are functionalized with polyethylene glycol‐cyclic arginine‐glycine‐aspartic acid tripeptide (PEG‐cRGD). After loading a chemotherapeutic drug (doxorubicin, DOX), MoTe₂‐PEG‐cRGD/DOX is used for combined photothermal therapy and chemotherapy. With the high photothermal conversion efficiency, MoTe₂‐PEG‐cRGD/DOX exhibits favorable cells killing ability under NIR irradiation. Owing to the cRGD‐mediated specific tumor targeting, MoTe₂‐PEG‐cRGD/DOX shows efficient accumulation in tumors to induce a strong tumor ablation effect. MoTe₂‐PEG‐cRGD nanosheets, which are relatively stable in the circulation, could be degraded under NIR ray. The in vitro and in vivo experimental results demonstrate that this theranostic nanoagent, which could accumulate in tumors to allow photothermal imaging and combined therapy, is readily degradable in normal organs to enable rapid excretion and avoid long‐term retention/toxicity, holding great potential to treat tumor effectively.