Manganese Dioxide Coated WS2@Fe3O4/sSiO2 Nanocomposites for pH‐Responsive MR Imaging and Oxygen‐Elevated Synergetic Therapy

Recently, the development of multifunctional theranostic nanoplatforms to realize tumor‐specific imaging and enhanced cancer therapy via responding or modulating the tumor microenvironment (TME) has attracted tremendous interests in the field of nanomedicine. Herein, tungsten disulfide (WS₂) nanoflakes with their surface adsorbed with iron oxide nanoparticles (IONPs) via self‐assembly are coated with silica and then subsequently with manganese dioxide (MnO₂), on to which polyethylene glycol (PEG) is attached. The obtained WS₂‐IO/S@MO‐PEG appears to be highly sensitive to pH, enabling tumor pH‐responsive magnetic resonance imaging with IONPs as the pH‐inert T2 contrast probe and MnO₂ as the pH‐sensitive T1 contrast probe. Meanwhile, synergistic combination tumor therapy is realized with such WS₂‐IO/S@MO‐PEG, by utilizing the strong near‐infrared light and X‐ray absorbance of WS₂ for photothermal therapy (PTT) and enhanced cancer radiotherapy (RT), respectively, as well as the ability of MnO₂ to decompose tumor endogenous H₂O₂ and relieve tumor hypoxia to further overcome hypoxia‐associated radiotherapy resistance. The combination of PTT and RT with WS₂‐IO/S@MO‐PEG results in a remarkable synergistic effect to destruct tumors. This work highlights the promise of developing multifunction nanocomposites for TME‐specific imaging and TME modulation, aiming at precision cancer synergistic treatment.     

Hemoglobin Nanocrystals for Drugs Free,Synergistic Theranostics of Colon Tumor (Small 8/2023)

The conventional approach in cancer nanomedicine involves advanced drug nanocarriers delivering preloaded therapeutics to targeted tumor sites to maximize drug efficiency. However, both cancer drugs and nanocarriers inevitably produce side effects and systemic toxicity. Herein, hemoglobin nanocrystals (HbC) as drug-free theranostic nanoformulations with the tumor microenvironment (TME) activated diagnostic and therapeutic abilities towards colon tumors are introduced. HbC can release Fe²⁺ oxidized to Fe³⁺ in the Fenton reaction with tumor endogenous H₂O₂, concurrently with the generation of cytotoxic hydroxyl radicals (•OH) that allow for chemodynamic therapy (CDT). Furthermore, in situ-produced Fe³⁺ reacts with colon tumor-abundant H₂S, resulting in the production of Fe_1−xS, which provides magnetic resonance imaging (MRI) contrast and allows for NIR light-inducible photothermal therapy (PTT). In vitro and in vivo studies revealed that HbC produced CDT towards 4T1 tumors, and MRI-guided, synergistically enhanced combination of CDT and PTT against H₂S abundant colon tumors (CT26), with negligible toxicity towards normal tissues, enlightening HbC as highly efficient and biocompatible TME activated theranostic nanoplatform specific against colon cancer without any traditional drugs and drug carriers.     

Novel PdPtCu Nanozymes for Reprogramming Tumor Microenvironment to Boost Immunotherapy Through Endoplasmic Reticulum Stress and Blocking IDO-Mediated Immune Escape

Breaking immunosuppressive tumor microenvironment (TME) has unique effects on inhibiting tumor growth and recurrence. Here, an endoplasmic reticulum (ER) targeted PdPtCu nanozyme (PNBCT^ER) is prepared to boost immunotherapy. First, PNBCT^ER has three kinds of enzyme activities, including catalase (CAT), glutathione oxidase (GSHOx), and peroxidase (POD)-like activities, which can reshape the TME. Second, PNBCT^ER kills tumor cells by photodynamic therapy (PDT) and photothermal therapy (PTT). Third, guided by T^ER, PNBCT^ER not only realizes the combination therapy of PDT, PTT and chemodynamic therapy (CDT), but also damages the ER of tumor cells and actives antitumor immune response, which breaks through the immune blockade of TME. Finally, the NLG919 blocks the tryptophan/kynurenine immune escape pathway and reverses the immunosuppressive TME. The strategy that reshaping the TME by enzyme catalysis and breaking immunosuppression provides a novel way for the application of combination therapy in tumor.     

Tumor pH‐Responsive Albumin/Polyaniline Assemblies for Amplified Photoacoustic Imaging and Augmented Photothermal Therapy

Tumor‐microenvironment‐responsive theranostics have great potential for precision diagnosis and effective treatment of cancer. Polyaniline (PANI) is the first reported pH‐responsive organic photothermal agent and is widely used as a theranostic agent. However, tumor pH‐responsive PANI‐based theranostic agents are not explored, mainly because the conversion from the emeraldine base (EB) to emeraldine salt (ES) state of PANI requires pH < 4, which is lower than tumor acidic microenvironment. Herein, a tumor pH‐responsive PANI‐based theranostic agent is designed and prepared for amplified photoacoustic imaging guided augmented photothermal therapy (PTT), through intermolecular acid–base reactions between carboxyl groups of bovine serum albumin (BSA) and imine moieties of PANI. The albumin/PANI assemblies (BSA–PANI) can convert from the EB to ES state at pH < 7, accompanied by the absorbance redshift from visible to near‐infrared region. Both in vitro and in vivo results demonstrate that tumor acidic microenvironment can trigger both the photoacoustic imaging (PAI) signal amplification and the PTT efficacy enhancement of BSA–PANI assemblies. This work not only highlights that BSA–PANI assemblies overcome the limitation of low‐pH protonation, but also provides a facile assembly strategy for a tumor pH‐responsive PANI‐based nanoplatform for cancer theranostics.     

A Multifunctional Cascade Bioreactor Based on Hollow‐Structured Cu2MoS4 for Synergetic Cancer Chemo‐Dynamic Therapy/Starvation Therapy/Phototherapy/Immunotherapy with Remarkably Enhanced Efficacy

The unique tumor microenvironment (TME) facilitates cancer proliferation and metastasis, and it is hard to cure cancer completely via monotherapy. Herein, a multifunctional cascade bioreactor based on hollow mesoporous Cu₂MoS₄ (CMS) loaded with glucose oxidase (GOx) is constructed for synergetic cancer therapy by chemo‐dynamic therapy (CDT)/starvation therapy/phototherapy/immunotherapy. The CMS harboring multivalent elements (Cu^1+/2+, Mo^4+/6+) exhibit Fenton‐like, glutathione (GSH) peroxidase‐like and catalase‐like activity. Once internalized into the tumor, CMS could generate ·OH for CDT via Fenton‐like reaction and deplete overexpressed GSH in TME to alleviate antioxidant capability of the tumors. Moreover, under hypoxia TME, the catalase‐like CMS could react with endogenous H₂O₂ to generate O₂ for activating the catalyzed oxidation of glucose by GOx for starvation therapy accompanied with the regeneration of H₂O₂. The regenerated H₂O₂ can devote to Fenton‐like reaction for realizing GOx‐catalysis‐enhanced CDT. Meanwhile, the CMS under 1064 nm laser irradiation shows remarkable tumor‐killing ability by phototherapy due to its excellent photothermal conversion efficiency (η = 63.3%) and cytotoxic superoxide anion (·O₂^?) generation performance. More importantly, the PEGylated CMS@GOx‐based synergistic therapy combined with checkpoint blockade therapy could elicit robust immune responses for both effectively ablating primary tumors and inhibiting cancer metastasis.     

A Tumor‐Microenvironment‐Activated Nanozyme‐Mediated Theranostic Nanoreactor for Imaging‐Guided Combined Tumor Therapy

Activatable theranostic agents that can be activated by tumor microenvironment possess higher specificity and sensitivity. Here, activatable nanozyme‐mediated 2,2′‐azino‐bis (3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS) loaded ABTS@MIL‐100/poly(vinylpyrrolidine) (AMP) nanoreactors (NRs) are developed for imaging‐guided combined tumor therapy. The as‐constructed AMP NRs can be specifically activated by the tumor microenvironment through a nanozyme‐mediated “two‐step rocket‐launching‐like” process to turn on its photoacoustic imaging signal and photothermal therapy (PTT) function. In addition, simultaneously producing hydroxyl radicals in response to the high H₂O₂ level of the tumor microenvironment and disrupting intracellular glutathione (GSH) endows the AMP NRs with the ability of enhanced chemodynamic therapy (ECDT), thereby leading to more efficient therapeutic outcome in combination with tumor‐triggered PTT. More importantly, the H₂O₂‐activated and acid‐enhanced properties enable the AMP NRs to be specific to tumors, leaving the normal tissues unharmed. These remarkable features of AMP NRs may open a new avenue to explore nanozyme‐involved nanoreactors for intelligent, accurate, and noninvasive cancer theranostics.     

An Activatable Phototheranostic Nanoplatform for Tumor Specific NIR-II Fluorescence Imaging and Synergistic NIR-II Photothermal-Chemodynamic Therapy

The phototheranostics in the second near-infrared window (NIR-II) have proven to be promising for the precise cancer theranostics. However, the non-responsive and “always on” imaging mode lacks the selectivity, leading to the poor diagnosis specificity. Herein, a tumor microenvironment (TME) activated NIR-II phototheranostic nanoplatform (Ag₂S-Fe(III)-DBZ Pdots, AFD NPs) is designed based on the principle of Förster resonance energy transfer (FRET). The AFD NPs are fabricated through self-assembly of Ag₂S QDs (NIR-II fluorescence probe) and ultra-small semiconductor polymer dots (DBZ Pdots, NIR-II fluorescence quencher) utilizing Fe(III) as coordination nodes. In normal tissues, the AFD NPs maintain in “off” state, due to the FRET between Ag₂S QDs and DBZ Pdots. However, the NIR-II fluorescence signal of AFD NPs can be rapidly “turn on” by the overexpressed GSH in tumor tissues, achieving a superior tumor-to-normal tissue (T/NT) signal ratio. Moreover, the released Pdots and reduced Fe(II) ions provide NIR-II photothermal therapy (PTT) and chemodynamic therapy (CDT), respectively. The GSH depletion and NIR-II PTT effect further aggravate CDT mediated oxidative damage toward tumors, achieving the synergistic anti-tumor therapeutic effect. The work provides a promising strategy for the development of TME activated NIR-II phototheranostic nanoprobes.     

Nanocatalysts‐Augmented and Photothermal‐Enhanced Tumor‐Specific Sequential Nanocatalytic Therapy in Both NIR‐I and NIR‐II Biowindows

The tumor microenvironment (TME) has been increasingly recognized as a crucial contributor to tumorigenesis. Based on the unique TME for achieving tumor‐specific therapy, here a novel concept of photothermal‐enhanced sequential nanocatalytic therapy in both NIR‐I and NIR‐II biowindows is proposed, which innovatively changes the condition of nanocatalytic Fenton reaction for production of highly efficient hydroxyl radicals (?OH) and consequently suppressing the tumor growth. Evidence suggests that glucose plays a vital role in powering cancer progression. Encouraged by the oxidation of glucose to gluconic acid and H₂O₂ by glucose oxidase (GOD), an Fe₃O₄/GOD‐functionalized polypyrrole (PPy)‐based composite nanocatalyst is constructed to achieve diagnostic imaging‐guided, photothermal‐enhanced, and TME‐specific sequential nanocatalytic tumor therapy. The consumption of intratumoral glucose by GOD leads to the in situ elevation of the H₂O₂ level, and the integrated Fe₃O₄ component then catalyzes H₂O₂ into highly toxic ?OH to efficiently induce cancer‐cell death. Importantly, the high photothermal‐conversion efficiency (66.4% in NIR‐II biowindow) of the PPy component elevates the local tumor temperature in both NIR‐I and NIR‐II biowindows to substaintially accelerate and improve the nanocatalytic disproportionation degree of H₂O₂ for enhancing the nanocatalytic‐therapeutic efficacy, which successfully achieves a remarkable synergistic anticancer outcome with minimal side effects.     

Programmable NIR‐II Photothermal‐Enhanced Starvation‐Primed Chemodynamic Therapy using Glucose Oxidase‐Functionalized Ancient Pigment Nanosheets

Chemodynamic therapy (CDT) has attracted considerable attention recently, but the poor reaction kinetics restrict its practical utility in clinic. Herein, glucose oxidase (GOx) functionalized ancient pigment nanosheets (SrCuSi₄O₁₀, SC) for programmable near‐infrared II (NIR‐II) photothermal‐enhanced starvation primed CDT is developed. The SC nanosheets (SC NSs) are readily exfoliated from SC bulk suspension in water and subsequently functionalized with GOx to form the nanocatalyst (denoted as SC@G NSs). Upon laser irradiation, the photothermal effect of SC NSs can enhance the catalytic activity of GOx for NIR‐II photothermal‐enhanced starvation therapy, which effectively eliminates intratumoral glucose and produces abundant hydrogen peroxide (H₂O₂). Importantly, the high photothermal‐conversion efficiency (46.3%) of SC@G NSs in second biological window permits photothermal therapy of deep‐seated tumors under the guidance of NIR‐II photoacoustic imaging. Moreover, the acidity amplification due to gluconic acid generation will in turn accelerate the degradation of SC NSs, facilitating the release of strontium (Sr) and copper (Cu) ions. Both the elevated H₂O₂ and the released ions will prime the Cu²⁺/Sr²⁺‐H₂O₂ reaction for enhanced CDT. Thus, a programmable NIR‐II photothermal‐enhanced starvation primed CDT is established to combat cancer with minimal side effects.     

Artificial Engineered Natural Killer Cells Combined with Antiheat Endurance as a Powerful Strategy for Enhancing Photothermal‐Immunotherapy Efficiency of Solid Tumors

Although photothermal therapy (PTT) is preclinically applied in solid tumor treatment, incomplete tumor removal of PTT and heat endurance of tumor cells induces significant tumor relapse after treatment, therefore lowering the therapeutic efficiency of PTT. Herein, a programmable therapeutic strategy that integrates photothermal therapeutic agents (PTAs), DNAzymes, and artificial engineered natural killer (A‐NK) cells for immunotherapy of hepatocellular carcinoma (HCC) is designed. The novel PTAs, termed as Mn‐CONASHs, with 2D structure are synthesized by the coordination of tetrahydroxyanthraquinone and Mn²⁺ ions. By further adsorbing polyetherimide/DNAzymes on the surface, the DNAzymes@Mn‐CONASHs exhibit excellent light‐to‐heat conversion ability, tumor microenvironment enhanced T₁‐MRI guiding ability, and antiheat endurance ability. Furthermore, the artificial engineered NK cells with HCC specific targeting TLS11a‐aptamer decoration are constructed for specifically eliminating any possible residual tumor cells after PTT, to systematically enhance the therapeutic efficacy of PTT and avoid tumor relapse. Taken together, the potential of A‐NK cells combined with antiheat endurance as a powerful strategy for immuno‐enhancing photothermal therapy efficiency of solid tumors is highlighted, and the current strategy might provide promising prospects for cancer therapy.     

Dynamically PEGylated and Borate‐Coordination‐Polymer‐Coated Polydopamine Nanoparticles for Synergetic Tumor‐Targeted,Chemo‐Photothermal Combination Therapy

Multifunctional nanomaterials with efficient tumor‐targeting and high antitumor activity are highly anticipated in the field of cancer therapy. In this work, a synergetic tumor‐targeted, chemo‐photothermal combined therapeutic nanoplatform based on a dynamically PEGylated, borate‐coordination‐polymer‐coated polydopamine nanoparticle (PDA@CP‐PEG) is developed. PEGylation on the multifunctional nanoparticles is dynamically achieved via the reversible covalent interaction between the surface phenylboronic acid (PBA) group and a catechol‐containing poly(ethylene glycol) (PEG) molecule. Due to the acid‐labile PBA/catechol complex and the weak‐acid‐stable PBA/sialic acid (SA) complex, the nanoparticles can exhibit a synergetic targeting property for the SA‐overexpressed tumor cells, i.e., the PEG‐caused “passive targeting” and PBA‐triggered “active targeting” under the weakly acidic tumor microenvironment. In addition, the photothermal effect of the polydopamine core and the doxorubicin‐loading capacity of the porous coordination polymer layer endow the nanoparticles with the potential for chemo‐photothermal combination therapy. As expected, the in vitro and in vivo studies both verify that the multifunctional nanoparticles possess relatively lower systematic toxicity, efficient tumor targeting ability, and excellent chemo‐photothermal activity for tumor inhibition. It is believed that these multifunctional nanoparticles with synergetic tumor targeting property and combined therapeutic strategies would provide an insight into the design of a high‐efficiency antitumor nanoplatform for potential clinical applications.     

A Metal–Polyphenol Network Coated Nanotheranostic System for Metastatic Tumor Treatments

As a characteristic trait of most tumor types, metastasis is the major cause of the death of patients. In this study, a photothermal agent based on gold nanorod is coated with metal (Gd³⁺)‐organic (polyphenol) network to realize combination therapy for metastatic tumors. This nanotheranostic system significantly enhances antitumor therapeutic effects in vitro and in vivo with the combination of photothermal therapy (PTT) and chemotherapy, also can remarkably prevent the invasion and metastasis due to the presence of polyphenol. After the treatment, an 81% decrease in primary tumor volumes and a 58% decrease in lung metastasis are observed. In addition, the good performance in magnetic resonance imaging, computerized tomography, and photothermal imaging of the nanotheranostic system can realize image‐guided therapy. The multifunctional nanotheranostic system will find a great potential in diagnosis and treatment integration in tumor treatments, and broaden the applications of PTT treatment.     

Photosensitizer‐Conjugated Albumin−Polypyrrole Nanoparticles for Imaging‐Guided In Vivo Photodynamic/Photothermal Therapy

Conjugated polymers with strong absorbance in the near‐infrared (NIR) region have been widely explored as photothermal therapy agents due to their excellent photostability and high photothermal conversion efficiency. Herein, polypyrrole (PPy) nanoparticles are fabricated by using bovine serum albumin (BSA) as the stabilizing agent, which if preconjugated with photosensitizer chlorin e6 (Ce6) could offer additional functionalities in both imaging and therapy. The obtained PPy@BSA‐Ce6 nanoparticles exhibit little dark toxicity to cells, and are able to trigger both photodynamic therapy (PDT) and photothermal therapy (PTT). As a fluorescent molecule that in the meantime could form chelate complex with Gd³⁺, Ce6 in PPy@BSA‐Ce6 nanoparticles after being labeled with Gd³⁺ enables dual‐modal fluorescence and magnetic resonance (MR) imaging, which illustrate strong tumor uptake of those nanoparticles after intravenous injection into tumor‐bearing mice. In vivo combined PDT and PTT treatment is then carried out after systemic administration of PPy@BSA‐Ce6, achieving a remarkably improved synergistic therapeutic effect compared to PDT or PTT alone. Hence, a rather simple one‐step approach to fabricate multifunctional nanoparticles based on conjugated polymers, which appear to be promising in cancer imaging and combination therapy, is presented.     

Double‐Targeting Explosible Nanofirework for Tumor Ignition to Guide Tumor‐Depth Photothermal Therapy

This study reports a double‐targeting “nanofirework” for tumor‐ignited imaging to guide effective tumor‐depth photothermal therapy (PTT). Typically, ≈30 nm upconversion nanoparticles (UCNP) are enveloped with a hybrid corona composed of ≈4 nm CuS tethered hyaluronic acid (CuS‐HA). The HA corona provides active tumor‐targeted functionality together with excellent stability and improved biocompatibility. The dimension of UCNP@CuS‐HA is specifically set within the optimal size window for passive tumor‐targeting effect, demonstrating significant contributions to both the in vivo prolonged circulation duration and the enhanced size‐dependent tumor accumulation compared with ultrasmall CuS nanoparticles. The tumors featuring hyaluronidase (HAase) overexpression could induce the escape of CuS away from UCNP@CuS‐HA due to HAase‐catalyzed HA degradation, in turn activating the recovery of initially CuS‐quenched luminescence of UCNP and also driving the tumor‐depth infiltration of ultrasmall CuS for effective PTT. This in vivo transition has proven to be highly dependent on tumor occurrence like a tumor‐ignited explosible firework. Together with the double‐targeting functionality, the pathology‐selective tumor ignition permits precise tumor detection and imaging‐guided spatiotemporal control over PTT operation, leading to complete tumor ablation under near infrared (NIR) irradiation. This study offers a new paradigm of utilizing pathological characteristics to design nanotheranostics for precise detection and personalized therapy of tumors.     

Transforming Weakness into Strength: Photothermal‐Therapy‐Induced Inflammation Enhanced Cytopharmaceutical Chemotherapy as a Combination Anticancer Treatment

A new synergistic treatment that combines photothermal therapy (PTT) and inflammation‐mediated active targeting (IMAT) chemotherapy based on cytopharmaceuticals is developed. During PTT, the photothermal tumor ablation is accompanied by an inflammatory effect and upregulation of inflammatory factors at the tumor site, which may accelerate tumor regeneration. Moreover, PTT‐induced inflammation can also recruit neutrophils (NEs) to the tumor site. To convert the disadvantages of PTT‐induced inflammation into strengths, NEs are investigated as cytopharmaceuticals for IMAT chemotherapy to further inhibit the tumor recurrence after PTT due to the chemotaxis of NEs to the inflammatory sites. In this study, PEGylated gold nanorods (PEG‐GNRs) are explored as the photothermal agent and paclitaxel‐loaded cytopharmaceuticals of NEs as the IMAT chemotherapeutic agent. PTT is conducted at 72 h postinjection of PEG‐GNRs, followed by cytopharmaceuticals for IMAT chemotherapy. It is demonstrated that the cytopharmaceuticals effectively accumulate in the tumor sites after PTT, which leads to a significant enhancement of antitumor efficacy and a reduction in systemic toxicity. These studies suggest that PTT‐induced inflammation further enhances the chemotherapy of cytopharmaceuticals, and the combination of PTT and IMAT chemotherapy may be a promising synergistic strategy for targeted cancer therapy.     

Mitochondria‐Targeted Polydopamine Nanocomposite with AIE Photosensitizer for Image‐Guided Photodynamic and Photothermal Tumor Ablation

Photodynamic therapy (PDT) and photothermal therapy (PTT) are two kinds of treatment for tumors. Herein, a new aggregation‐induced emission (AIE)gen (MeO‐TPE‐indo, MTi) is synthesized with a D–π–A conjugated structure. MTi, which has an electron donor and an acceptor on a tetraphenylethene (TPE) conjugated skeleton, can induce the effective generation of reactive oxygen species (ROS) for PDT. With the guide of the indolium group, MTi can target and image mitochondrion selectively. In order to get good dispersion in water and long‐time retention in tumors, MTi is modified on the surface of polydopamine nanoparticles (PDA NPs) to form the nanocomposite (PDA‐MeO‐TPE‐indo, PMTi ) by π–π and hydrogen interactions. PMTi is a nanoscale composite for imaging‐guided PDT and PTT in tumor treatment, which is constructed with AIEgens and PDA for the first time. The organic functional molecules are combined with nanomaterials for building a multifunctional diagnosis and treatment platform by utilizing the advantages of both sides.     

Glutathione Induced Transformation of Partially Hollow Gold–Silver Nanocages for Cancer Diagnosis and Photothermal Therapy

Gold–silver nanocages (GSNCs) are widely used in cancer imaging and therapy due to excellent biocompatibility, internal hollow structures, and tunable optical properties. However, their possible responses toward the tumor microenvironment are still not well understood. In this study, it is demonstrated that a kind of relatively small sized (35 nm) and partially hollow GSNCs (absorbance centered at 532 nm) can enhance the intrinsic photoacoustic imaging performances for blood vessels around tumor sites. More importantly, the high concentration of glutathione around the tumor cells' microenvironment may induce the aggregation, disintegration, and agglomeration of these GSNCs sequentially, allowing significant shifts in the absorbance spectrum of GSNCs to the near‐infrared (NIR) region. This enhanced absorbance in the NIR region entails the significant photothermal therapy (PTT) effect. In vivo experiments, including photoacoustic microscopy (PAM) for cancer diagnosis and PTT in tumor model mice, also show coincident consequences. Taken together, the slightly hollow GSNCs may assist PAM‐based tumor diagnosis and induce a tumor targeted PTT effect. This work paves a new avenue for the development of an alternative tumor diagnostic and therapeutic strategy.     

Molecular Targeting‐Mediated Mild‐Temperature Photothermal Therapy with a Smart Albumin‐Based Nanodrug

Photothermal therapy (PTT) usually requires hyperthermia >50 °C for effective tumor ablation, which inevitably induces heating damage to the surrounding normal tissues/organs. Moreover, low tumor retention and high liver accumulation are the two main obstacles that significantly limit the efficacy and safety of many nanomedicines. To solve these problems, a smart albumin‐based tumor microenvironment‐responsive nanoagent is designed via the self‐assembly of human serum albumin (HSA), dc‐IR825 (a cyanine dye and a photothermal agent), and gambogic acid (GA, a heat shock protein 90 (HSP90) inhibitor and an anticancer agent) to realize molecular targeting‐mediated mild‐temperature PTT. The formed HSA/dc‐IR825/GA nanoparticles (NPs) can escape from mitochondria to the cytosol through mitochondrial disruption under near‐infrared (NIR) laser irradiation. Moreover, the GA molecules block the hyperthermia‐induced overexpression of HSP90, achieving the reduced thermoresistance of tumor cells and effective PTT at a mild temperature (<45 °C). Furthermore, HSA/dc‐IR825/GA NPs show pH‐responsive charge reversal, effective tumor accumulation, and negligible liver deposition, ultimately facilitating synergistic mild‐temperature PTT and chemotherapy. Taken together, the NIR‐activated NPs allow the release of molecular drugs more precisely, ablate tumors more effectively, and inhibit cancer metastasis more persistently, which will advance the development of novel mild‐temperature PTT‐based combination strategies.     

Photoconversion‐Tunable Fluorophore Vesicles for Wavelength‐Dependent Photoinduced Cancer Therapy

Photoconversion tunability of fluorophore dye is of great interest in cancer nanomedicine such as fluorescence imaging, photodynamic therapy (PDT), and photothermal therapy (PTT). Herein, this paper reports wavelength‐dependent photoconversional polymeric vesicles of boron dipyrromethene (Bodipy) fluorophore for either PDT under 660 nm irradiation or PTT under 785 nm irradiation. After being assembled within polymeric vesicles at a high drug loading, Bodipy molecules aggregate in the conformations of both J‐type and H‐type, thereby causing red‐shifted absorption into near‐infrared region, ultralow radiative transition, and ideal resistance to photobleaching. Such vesicles further possess enhanced blood circulation, preferable tumor accumulation, as well as superior cell uptake as compared to free Bodipy. In particular, the vesicles mainly generate abundant intracellular singlet oxygen for PDT treatment under 660 nm irradiation, while they primarily produce a potent hyperthermia for PTT with tumor ablation through singlet oxygen‐synergized photothermal necrosis under 785 nm irradiation. This approach provides a facile and general strategy to tune photoconversion characteristics of fluorophore dyes for wavelength‐dependent photoinduced cancer therapy.     

NIR‐Responsive Polycationic Gatekeeper‐Cloaked Hetero‐Nanoparticles for Multimodal Imaging‐Guided Triple‐Combination Therapy of Cancer

Responsive multifunctional organic/inorganic nanohybrids are promising for effective and precise imaging‐guided therapy of cancer. In this work, a near‐infrared (NIR)‐triggered multifunctional nanoplatform comprising Au nanorods (Au NRs), mesoporous silica, quantum dots (QDs), and two‐armed ethanolamine‐modified poly(glycidyl methacrylate) with cyclodextrin cores (denoted as CD‐PGEA) has been successfully fabricated for multimodal imaging‐guided triple‐combination treatment of cancer. A hierarchical hetero‐structure is first constructed via integration of Au NRs with QDs through a mesoporous silica intermediate layer. The X‐ray opacity and photoacoustic (PA) property of Au NRs are utilized for tomography (CT) and PA imaging, and the imaging sensitivity is further enhanced by the fluorescent QDs. The mesoporous feature of silica allows the loading of a typical antitumor drug, doxorubicin (DOX), which are sealed by the polycationic gatekeepers, low toxic hydroxyl‐rich CD‐PGEA/pDNA complexes, realizing the co‐delivery of drug and gene. The photothermal effect of Au NRs is utilized for photothermal therapy (PTT). More interestingly, such photothermal effect also induces a cascade of NIR‐triggered release of DOX through the facilitated detachment of CD‐PGEA gatekeepers for controlled chemotherapy. The resultant chemotherapy and gene therapy for glioma tumors are complementary for the efficiency of PTT. This work presents a novel responsive multifunctional imaging‐guided therapy platform, which combines fluorescent/PA/CT imaging and gene/chemo/photothermal therapy into one nanostructure.