Dual pH/ROS‐Responsive Nanoplatform with Deep Tumor Penetration and Self‐Amplified Drug Release for Enhancing Tumor Chemotherapeutic Efficacy

Poor deep tumor penetration and incomplete intracellular drug release remain challenges for antitumor nanomedicine application in clinical settings. Herein, a nanomedicine (RLPA‐NPs) is developed that can achieve prolonged blood circulation, deep tumor penetration, active‐targeting of cancer cells, endosome/lysosome escape, and intracellular selectivity self‐amplified drug release for effective drug delivery. The RLPA‐NPs are constructed by encapsulation of a pH‐sensitive polymer octadecylamine‐poly(aspartate‐1‐(3‐aminopropyl) imidazole) (OA‐P(Asp‐API)) and a ROS‐generation agent, β‐Lapachone (Lap), in micelles assembled by the tumor‐penetration peptide internalizing RGD (iRGD)‐modified ROS‐responsive paclitaxel (PTX)‐prodrug. iRGD could promote RLPA‐NPs penetration into deep tumor tissue, and specific targeting to cancer cells. After internalization by cancer cells through receptor‐mediated endocytosis, OA‐P(Asp‐API) can rapidly protonate in the endosome's acidic environment, resulting in RLPA‐NPs escape from the endosome through the “proton sponge effect”. At the same time, the RLPA‐NPs micelle disassembles, releasing Lap and PTX‐prodrug. Subsequently, the released Lap could generate ROS, consequently amplifying and accelerating PTX release to kill tumor cells. The in vitro and in vivo studies demonstrated that RLPA‐NPs can significantly improve the therapeutic effect compared to control groups. Therefore, RLPA‐NPs are a promising nanoplatform for overcoming multiple physiological and pathological barriers to enhance drug delivery.     

An NIR‐Fluorophore‐Based Therapeutic Endoplasmic Reticulum Stress Inducer

The endoplasmic reticulum (ER) stress signaling or unfolded protein response (UPR) is a common feature of many human diseases, including cancer. Excessive activation of ER stress directly induces cell death, holding a new promising strategy for the therapeutic intervention of cancer. Current ER‐stress‐inducing agents mainly target UPR components or proteasomes, which exert limited treatment efficacy and undesired side effects due to unselective ER stress and poor tumor‐specific distribution. In this study, a unique near‐infrared (NIR) fluorophore, IR‐34, is synthesized and identified to selectively and efficiently trigger tumoricidal ER stress by targeting the mitochondrial protein NDUFS1. IR‐34 is demonstrated to specifically accumulate in living cancer cells for tumor NIR imaging and drastically inhibit tumor growth and recurrence without causing apparent toxicity. Thus, this multifunctional NIR fluorophore may represent a novel theranostic agent for tumor imaging‐guided treatment and also strengthens the idea that mitochondria could be a useful target for therapeutic ER stress in cancer cells.     

Enhanced Photothermal Therapy through the In Situ Activation of a Temperature and Redox Dual‐Sensitive Nanoreservoir of Triptolide

Photothermal therapy (PTT) has attracted tremendous attention due to its noninvasiveness and localized treatment advantages. However, heat shock proteins (HSPs) associated self‐preservation mechanisms bestow cancer cells thermoresistance to protect them from the damage of PTT. To minimize the thermoresistance of cancer cells and improve the efficacy of PTT, an integrated on‐demand nanoplatform composed of a photothermal conversion core (gold nanorod, GNR), a cargo of a HSPs inhibitor (triptolide, TPL), a mesoporous silica based nanoreservoir, and a photothermal and redox di‐responsive polymer shell is developed. The nanoplatform can be enriched in the tumor site, and internalized into cancer cells, releasing the encapsulated TPL under the trigger of intracellular elevated glutathione and near‐infrared laser irradiation. Ultimately, the liberated TPL could diminish thermoresistance of cancer cells by antagonizing the PTT induced heat shock response via multiple mechanisms to maximize the PTT effect for cancer treatment.     

Mitochondria‐Targeting Magnetic Composite Nanoparticles for Enhanced Phototherapy of Cancer

Photothermal therapy (PTT) and photodynamic therapy (PDT) are promising cancer treatment modalities in current days while the high laser power density demand and low tumor accumulation are key obstacles that have greatly restricted their development. Here, magnetic composite nanoparticles for dual‐modal PTT and PDT which have realized enhanced cancer therapeutic effect by mitochondria‐targeting are reported. Integrating PTT agent and photosensitizer together, the composite nanoparticles are able to generate heat and reactive oxygen species (ROS) simultaneously upon near infrared (NIR) laser irradiation. After surface modification of targeting ligands, the composite nanoparticles can be selectively delivered to the mitochondria, which amplify the cancer cell apoptosis induced by hyperthermia and the cytotoxic ROS. In this way, better photo therapeutic effects and much higher cytotoxicity are achieved by utilizing the composite nanoparticles than that treated with the same nanoparticles missing mitochondrial targeting unit at a low laser power density. Guided by NIR fluorescence imaging and magnetic resonance imaging, then these results are confirmed in a humanized orthotropic lung cancer model. The composite nanoparticles demonstrate high tumor accumulation and excellent tumor regression with minimal side effect upon NIR laser exposure. Therefore, the mitochondria‐targeting composite nanoparticles are expected to be an effective phototherapeutic platform in oncotherapy.     

Light‐Triggered Biomimetic Nanoerythrocyte for Tumor‐Targeted Lung Metastatic Combination Therapy of Malignant Melanoma

Red blood cell (RBC) membrane‐cloaked nanoparticles, reserving the intact cell membrane structure and membrane protein, can gain excellent cell‐specific functions such as long blood circulation and immune escape, providing a promising therapy nanoplatform for drug delivery. Herein, a novel RBC membrane biomimetic combination therapeutic system with tumor targeting ability is constructed by embedding bovine serum albumin (BSA) encapsulated with 1,2‐diaminocyclohexane‐platinum (II) (DACHPt) and indocyanine green (ICG) in the targeting peptide‐modified erythrocyte membrane (R‐RBC@BPtI) for enhancing tumor internalization and synergetic chemophototherapy. R‐RBC@BPtI displays excellent stability and high encapsulation efficiency with multiple cores enveloped in the membrane. Benefited from the stealth functionality and targeting modification of erythrocyte membranes, R‐RBC@BPtI can significantly promote tumor targeting and cellular uptake. Under the near‐infrared laser stimuli, R‐RBC@BPtI presents remarkable instability by singlet oxygen and heat‐mediated cleavage so as to trigger effective drug release, thereby achieving deep penetration and accumulation of DACHPt and ROS in the tumor site. Consequently, R‐RBC@BPtI with tumor‐specific targeting ability accomplishes remarkable ablation of tumors and suppressed lung metastasis in vivo by photothermal and chemotherapy combined ablation under phototriggering. This research provides a novel strategy of targeted biomimetic nanoplatforms for combined cancer chemotherapy–phototherapy.     

Dye‐Anchored MnO Nanoparticles Targeting Tumor and Inducing Enhanced Phototherapy Effect via Mitochondria‐Mediated Pathway

Phototherapy is a promising treatment method for cancer therapy. However, the various factors have greatly restricted phototherapy development, including the poor accumulation of photosensitizer in tumor, hypoxia in solid tumor tissue and systemic phototoxicity. Herein, a mitochondrial‐targeted multifunctional dye‐anchored manganese oxide nanoparticle (IR808@MnO NP) is developed for enhancing phototherapy of cancer. In this nanoplatform, IR808 as a small molecule dye acts as a tumor targeting ligand to make IR808@MnO NPs with capacity to actively target tumor cells and relocate finally in the mitochondria. Meanwhile, continuous production of oxygen (O₂) and regulation of pH induced by the high reactivity and specificity of MnO NPs toward mitochondrial endogenous hydrogen peroxide (H₂O₂) could effectively modulate tumor hypoxia and lessen the tumor subacid environment. Large amounts of reactive oxide species (ROS) are generated during the reaction process between H₂O₂ and MnO NPs. Furthermore, under laser irradiation, IR808 in IR808@MnO NPs turns O₂ into a highly toxic singlet oxygen (¹O₂) and generates hyperthermia. The results indicate that IR808@MnO NPs have the high efficiency of specific targeting of tumors, relieving tumor subacid environment, improving the tumor hypoxia environment, and generating large amounts of ROS to kill tumor cells. It is expected to have a wide application in treating cancer.     

Synergistic Amplification of Oxidative Stress–Mediated Antitumor Activity via Liposomal Dichloroacetic Acid and MOF‐Fe2+

Cancer cells are susceptible to oxidative stress; therefore, selective elevation of intracellular reactive oxygen species (ROS) is considered as an effective antitumor treatment. Here, a liposomal formulation of dichloroacetic acid (DCA) and metal–organic framework (MOF)‐Fe²⁺ (MD@Lip) has been developed, which can efficiently stimulate ROS‐mediated cancer cell apoptosis in vitro and in vivo. MD@Lip can not only improve aqueous solubility of octahedral MOF‐Fe²⁺, but also generate an acidic microenvironment to activate a MOF‐Fe²⁺‐based Fenton reaction. Importantly, MD@Lip promotes DCA‐mediated mitochondrial aerobic oxidation to increase intracellular hydrogen peroxide (H₂O₂), which can be consequently converted to highly cytotoxic hydroxyl radicals (?OH) via MOF‐Fe²⁺, leading to amplification of cancer cell apoptosis. Particularly, MD@Lip can selectively accumulate in tumors, and efficiently inhibit tumor growth with minimal systemic adverse effects. Therefore, liposome‐based combination therapy of DCA and MOF‐Fe²⁺ provides a promising oxidative stress–associated antitumor strategy for the management of malignant tumors.     

Prodrug‐Based Versatile Nanomedicine for Enhancing Cancer Immunotherapy by Increasing Immunogenic Cell Death

Nanoparticle‐based tumor immunotherapy has emerged to show great potential for simultaneously regulating the immunosuppressive tumor microenvironment, reducing the unpleasant side effects, and activating tumor immunity. Herein, an excipient‐free glutathione/pH dual‐responsive prodrug nanoplatform is reported for immunotherapy, simply by sequentially liberating 5‐aminolevulinic acid and immunogenically inducing doxorubicin drug molecules, which can leverage the acidity and reverse tumor microenvironment. The obtained nanoplatform effectively boosts the immune system by promoting dendritic cell maturation and reducing the number of immune suppressive immune cells, which shows the enhanced adjunctive effect of anti‐programmed cell death protein 1 therapy. Overall, the prodrug‐based immunotherapy nanoplatform may offer a reliable strategy for improving synergistic antitumor efficacy.     

Highly Efficient Photosensitizers with Far‐Red/Near‐Infrared Aggregation‐Induced Emission for In Vitro and In Vivo Cancer Theranostics

Fluorescence‐imaging‐guided photodynamic therapy has emerged as a promising protocol for cancer theranostics. However, facile preparation of such a theranostic material for simultaneously achieving bright emission with long wavelength, high‐performance reactive oxygen species (ROS) generation, and good targeting‐specificity of cancer cells, is highly desirable but remains challenging. In this study, a novel type of far‐red/near‐infrared‐emissive fluorescent molecules with aggregation‐induced emission (AIE) characteristics is synthesized through a few steps reaction. These AIE luminogens (AIEgens) possess simple structures, excellent photostabilities, large Stokes shifts, bright emission, and good biocompatibilities. Meanwhile, their ROS generation is extremely efficient with up to 90.7% of ROS quantum yield, which is far superior to that of some popularly used photosensitizers. Importantly, these AIEgens are able to selectively target and ablate cancer cells over normal cells without the aid of any extra targeting ligands. Rather than using laser light, one of the presented AIEgens (MeTTPy) shows a remarkable tumor‐targeting photodynamic therapeutic effect by using an ultralow‐power lamp light (18 mW cm^?2). This study thus not only extends the applications scope of AIEgens, but also offers useful insights into designing a new generation of cancer theranostics.     

Self‐Destruction of Cancer Induced by Ag2S Amorphous Nanodots

Studies on distinctive performances and novel applications of amorphous inorganic nanomaterials are becoming attractive. Herein, Ag₂S amorphous and crystalline nanodots (ANDs and CNDs) are prepared via facile methods. In vitro and in vivo studies indicate that Ag₂S ANDs, rather than CNDs, can induce the self‐destruction of tumors, which can be attributed to their distinctive chemical properties, e.g., the higher electrochemical active surface area and lower redox potential well matching with the redox reaction requirement in the tumor microenvironment. Ag₂S ANDs can be oxidized by intracellular reactive oxygen species (ROS) to release Ag⁺, which further stimulates high generation of intracellular ROS. This mutual stimulation damages the mitochondria, induces apoptosis, and leads to the self‐destruction of the tumor. Moreover, Ag₂S ANDs do not show observable in vitro and in vivo side effects. These findings provide a promising self‐destructive strategy for cancer therapy by utilizing distinctive chemical properties of inorganic nanomaterials, while avoiding complicated external assistance.     

Peptide Nanotube‐Templated Biomineralization of Cu2−xS Nanoparticles for Combination Treatment of Metastatic Tumor

1D peptide nanostructures (i.e., peptide nanotubes, PNTs) exhibit tunable chemo‐physical properties and functions such as improved tissue adhesion, increased cellular uptake, and elongated blood circulation. In this study, the application of PNTs as a desirable 1D template for biomineralization of Cu_2?xS nanoparticles (Cu_2?xS NPs, x = 1–2) is reported. Monodisperse Cu_2?xS NPs are uniformly coated on the peptide nanotubes owing to the specific high binding affinity of Cu ions to the imidazole groups exposed on the surface of nanotubes. The Cu_2?xS NP–coated PNTs are further covalently grafted with an oxaliplatin prodrug (Pt–CuS–PNTs) to construct a versatile nanoplatform for combination cancer therapy. Upon 808 nm laser illumination, the nanoplatform induces significant hyperthermia effect and elicits reactive oxygen species generation through electron transfer and Fenton‐like reaction. It is demonstrated that the versatile nanoplatform dramatically inhibits tumor growth and lung metastasis of melanoma in a B16‐F10 melanoma tumor‐bearing mouse model by combined photo‐ and chemotherapy. This study highlights the ability of PNTs for biomineralization of metal ions and the promising potential of such nanoplatforms for cancer treatment.     

Cytotoxicity of BSA‐Stabilized Gold Nanoclusters: In Vitro and In Vivo Study

Gold nanoclusters (Au NCs) are one of the most promising fluorescent nanomaterials for bioimaging, targeting, and cancer therapy due to their tunable optical properties, yet their biocompatibility still remains unclear. Herein, the cytotoxicity of bovine serum albumin (BSA)‐stabilized Au NCs is studied by using three tumor cell lines and two normal cell lines. The results indicate that Au NCs induce the decline of cell viabilities of different cell lines to varying degrees in a dose‐ and time‐dependent manner, and umbilical vein endothelial cells which had a higher intake of Au NCs than melanoma cells show more toxicity. Addition of free BSA to BSA‐Au NCs solutions can relieve the cytotoxicity, implying that BSA can prevent cell damage. Moreover, Au NCs increase intracellular reactive oxygen species (ROS) production, further causing cell apoptosis. Furthermore, N‐acetylcysteine, a ROS scavenger, partially reverses Au NCs‐induced cell apoptosis and cytotoxicity, indicating that ROS might be one of the primary reasons for the toxicity of BSA‐Au NCs. Surprisingly, Au NCs with concentrations of 5 and 20 nM significantly inhibit tumor growth in the xenograft mice model of human liver cancer, which might provide a new avenue for the design of anti‐cancer drug delivery vehicles.     

A Novel Top‐Down Synthesis of Ultrathin 2D Boron Nanosheets for Multimodal Imaging‐Guided Cancer Therapy

Single atom nonmetal 2D nanomaterials have shown considerable potential in cancer nanomedicines, owing to their intriguing properties and biocompatibility. Herein, ultrathin boron nanosheets (B NSs) are prepared through a novel top‐down approach by coupling thermal oxidation etching and liquid exfoliation technologies, with controlled nanoscale thickness. Based on the PEGylated B NSs, a new photonic drug delivery platform is developed, which exhibits multiple promising features for cancer therapy and imaging, including: i) efficient NIR‐light‐to‐heat conversion with a high photothermal conversion efficiency of 42.5%, ii) high drug‐loading capacity and triggered drug release by NIR light and moderate acidic pH, iii) strong accumulation at tumor sites, iv) multimodal imaging properties (photoacoustic, photothermal, and fluorescence imaging), and v) complete tumor ablation and excellent biocompatibility. As far as it is known, this is the first report on the top‐down fabrication of ultrathin 2D B NSs by the combined thermal oxidation etching and liquid exfoliation, as well as their application as a multimodal imaging‐guided drug delivery platform. The newly prepared B NSs are also expected to provide a robust and useful 2D nanoplatform for various biomedical applications.     

Programmed Nanococktail for Intracellular Cascade Reaction Regulating Self‐Synergistic Tumor Targeting Therapy

In this work, a ZnO based nanococktail with programmed functions is designed and synthesized for self‐synergistic tumor targeting therapy. The nanococktail can actively target tumors via specific interaction of hyaluronic acid (HA) with CD44 receptors and respond to HAase‐rich tumor microenvironment to induce intracellular cascade reaction for controlled therapy. The exposed cell‐penetrating peptide (R8) potentiates the cellular uptake of therapeutic nanoparticles into targeted tumor cells. Then ZnO cocktail will readily degrade in acidic endo/lysosomes and induce the production of desired reactive oxygen species (ROS) in situ. The destructive ROS not only leads to serious cell damage but also triggers the on‐demand drug release for precise chemotherapy, thus achieving enhanced antitumor efficiency synergistically. After tail vein injection of ZnO cocktail, a favorable tumor apoptosis rate (71.2 ± 8.2%) is detected, which is significantly superior to that of free drug, doxorubicin (12.9 ± 5.2%). Both in vitro and in vivo studies demonstrate that the tailor‐made ZnO cocktail with favorable biocompatibility, promising tumor specificity, and self‐synergistically therapeutic capacity opens new avenues for cancer therapy.     

Glutathione Depletion in a Benign Manner by MoS2‐Based Nanoflowers for Enhanced Hypoxia‐Irrelevant Free‐Radical‐Based Cancer Therapy

Tumor hypoxia significantly diminishes the efficacy of reactive oxygen species (ROS)‐based therapy, mainly because the generation of ROS is highly oxygen dependent. Recently reported hypoxia‐irrelevant radical initiators (AIBIs) exhibit promising potential for cancer therapy under different oxygen tensions. However, overexpressed glutathione (GSH) in cancer cells would potently scavenge the free radicals produced from AIBI before their arrival to the specific site and dramatically limit the therapeutic efficacy. A synergistic antitumor platform (MoS₂@AIBI‐PCM nanoflowers) is constructed by incorporating polyethylene‐glycol‐functionalized molybdenum disulfide (PEG‐MoS₂) nanoflowers with azo initiator and phase‐change material (PCM). Under near‐infrared laser (NIR) irradiation, the photothermal feature of PEG‐MoS₂ induces the decomposition of AIBI to produce free radicals. Furthermore, PEG‐MoS₂ can facilitate GSH oxidation without releasing toxic metal ions, greatly promoting tumor apoptosis and avoiding the introduction of toxic metal ions. This is the first example of the use of intelligent MoS₂‐based nanoflowers as a benign GSH scavenger for enhanced cancer treatment.     

Efficacy Dependence of Photodynamic Therapy Mediated by Upconversion Nanoparticles: Subcellular Positioning and Irradiation Productivity

Singlet oxygen (¹O₂), as an important kind of reactive oxygen species (ROS) and main therapeutic agent in photodynamic therapy (PDT), only have a half‐life of 40 ns and an effective radius of 20 nm, which cause significant obstacles for improving PDT efficacy. In this work, novel upconversion nanoparticle (UCN)‐based nanoplatforms are developed with a minimized distance between UCNs and a photosensitizer, protoporphyrin IX (PpIX), and a controllable payload of PpIX, to enhance and control ROS production. The ability of the nanoplatform to target different subcellular organelles such as cell membrane and mitochondria is demonstrated via surface modification of the nanoplatform with different targeting ligands. The results show that the mitochondria‐targeting nanoplatforms result in significantly increased capability of both tumor cell killing and inhibition of tumor growth. Subcellular targeting of nanoparticles leads to the death of cancer cells in different manners. However, the efficiency of ROS generation almost have no influence on the tumor cell viability during the period of evaluation. These findings suggest that specific subcellular targeting of the nanoplatforms enhances the PDT efficacy more effectively than the increase of ROS production, and may shed light on future novel designs of effective and controllable PDT nanoplatforms.     

Chemo/Photoacoustic Dual Therapy with mRNA‐Triggered DOX Release and Photoinduced Shockwave Based on a DNA‐Gold Nanoplatform

A multifunctional nanoparticle based on gold nanorod (GNR), utilizing mRNA triggered chemo‐drug release and near‐infrared photoacoustic effect, is developed for a combined chemo‐photoacoustic therapy. The constructed nanoparticle (GNR‐DNA/FA:DOX) comprises three functional components: (i) GNR as the drug delivery platform and photoacoustic effect enhancer; (ii) toehold‐possessed DNA dressed on the GNR to load doxorubicin (DOX) to implement a tumor cell specific chemotherapy; and (iii) folate acid (FA) modified on GNR to guide the nanoparticle to target tumor cells. The results show that, upon an effective and specific delivery of the nanoparticles to the tumor cells with overexpressed folate receptors, the cytotoxic DOX loaded on the GNR‐DNA nanoplatform can be released through DNA displacement reaction in melanoma‐associated antigen gene mRNA expressed cells. With 808 nm pulse laser irradiation, the photoacoustic effect of the GNR leads to a direct physical damage to the cells. The combined treatment of the two modalities can effectively destroy tumor cells and eradicate the tumors with two distinctively different and supplementing mechanisms. With the nanoparticle, photoacoustic imaging is successfully performed in situ to monitor the drug distribution and tumor morphology for therapeutical guidance. With further in‐depth investigation, the proposed nanoparticle may provide an effective and safe alternative cancer treatment modality.     

Toxic Reactive Oxygen Species Enhanced Synergistic Combination Therapy by Self‐Assembled Metal‐Phenolic Network Nanoparticles

Engineering functional nanomaterials with high therapeutic efficacy and minimum side effects has increasingly become a promising strategy for cancer treatment. Herein, a reactive oxygen species (ROS) enhanced combination chemotherapy platform is designed via a biocompatible metal‐polyphenol networks self‐assembly process by encapsulating doxorubicin (DOX) and platinum prodrugs in nanoparticles. Both DOX and platinum drugs can activate nicotinamide adenine dinucleotide phosphate oxidases, generating superoxide radicals (O₂^??). The superoxide dismutase‐like activity of polyphenols can catalyze H₂O₂ generation from O₂^??. Finally, the highly toxic HO^? free radicals are generated by a Fenton reaction. The ROS HO^? can synergize the chemotherapy by a cascade of bioreactions. Positron emission tomography imaging of ⁸⁹Zr‐labeled as‐prepared DOX@Pt prodrug Fe³⁺ nanoparticles (DPPF NPs) shows prolonged blood circulation and high tumor accumulation. Furthermore, the DPPF NPs can effectively inhibit tumor growth and reduce the side effects of anticancer drugs. This study establishes a novel ROS promoted synergistic nanomedicine platform for cancer therapy.     

Bioinspired Multivalent Peptide Nanotubes for Sialic Acid Targeting and Imaging‐Guided Treatment of Metastatic Melanoma

Tumor metastasis is considered a major cause of cancer‐related human mortalities. However, it still remains a formidable challenge in clinics. Herein, a bioinspired multivalent nanoplatform for the highly effective treatment of the metastatic melanoma is reported. The versatile nanoplatform is designed by integrating indocyanine green and a chemotherapeutic drug (7‐ethyl‐10‐hydroxycamptothecin) into phenylboronic acid (PBA)‐functionalized peptide nanotubes (termed as I/S‐PPNTs). I/S‐PPNTs precisely target tumor cells through multivalent interaction between PBA and overexpressed sialic acid on the tumor surface in order to achieve imaging‐guided combination therapy. It is demonstrated that I/S‐PPNTs are efficiently internalized by the B16‐F10 melanoma cells in vitro in a PBA grafting density–dependent manner. It is further shown that I/S‐PPNTs specifically accumulate and deeply penetrate into both the subcutaneous and lung metastatic B16‐F10 melanoma tumors. More importantly, I/S‐PPNT‐mediated combination chemo‐ and photodynamic therapy efficiently eradicates tumor and suppresses the lung metastasis of B16‐F10 melanoma in an immunocompetent C57BL/6 mouse model. The results highlight the promising potential of the multivalent peptide nanotubes for active tumor targeting and imaging‐guided cancer therapy.     

Hydrogen Peroxide Responsive Iron–Based Nanoplatform for Multimodal Imaging–Guided Cancer Therapy

Cancer multimodal phototherapy triggered by hydrogen peroxide has attracted widespread attention as a dominating strategy to increase phototherapeutic efficiency. Herein, a hydrogen peroxide responsive iron oxide nanoplatform, with the diameter of about 50 nm, is fabricated to intracellularly trigger the Fenton reaction and achieve synergistic photodynamic therapy and photothermal therapy. The nanoplatform based on iron oxide nanoparticles is decorated with indocyanine green (ICG, photosensitizer) and hyaluronic acid (HA, targeting molecular) through electrostatic interaction, thus the as‐prepared nanoplatform (IONPs‐ICG‐HA) exhibits excellent active targeting ability and biocompatibility. More importantly, it can effectively utilize the intratumoral overproduced hydrogen peroxide to generate reactive oxygen species for cancer cell killing via intracellular Fenton reactions. In vitro and in vivo experiments reveal that the IONPs‐ICG‐HA nanocomposites realize effective photoacoustic/photothermal/fluorescence imaging–guided phototherapy, leading to promising hydrogen peroxide responsive cancer theranostics.