A Mussel‐Inspired Persistent ROS‐Scavenging,Electroactive, and Osteoinductive Scaffold Based on Electrochemical‐Driven In Situ Nanoassembly

Conductive polymers are promising for bone regeneration because they can regulate cell behavior through electrical stimulation; moreover, they are antioxidative agents that can be used to protect cells and tissues from damage originating from reactive oxygen species (ROS). However, conductive polymers lack affinity to cells and osteoinductivity, which limits their application in tissue engineering. Herein, an electroactive, cell affinitive, persistent ROS‐scavenging, and osteoinductive porous Ti scaffold is prepared by the on‐surface in situ assembly of a polypyrrole‐polydopamine‐hydroxyapatite (PPy‐PDA‐HA) film through a layer‐by‐layer pulse electrodeposition (LBL‐PED) method. During LBL‐PED, the PPy‐PDA nanoparticles (NPs) and HA NPs are in situ synthesized and uniformly coated on a porous scaffold from inside to outside. PDA is entangled with and doped into PPy to enhance the ROS scavenging rate of the scaffold and realize repeatable, efficient ROS scavenging over a long period of time. HA and electrical stimulation synergistically promote osteogenic cell differentiation on PPy‐PDA‐HA films. Ultimately, the PPy‐PDA‐HA porous scaffold provides excellent bone regeneration through the synergistic effects of electroactivity, cell affinity, and antioxidative activity of the PPy‐PDA NPs and the osteoinductivity of HA NPs. This study provides a new strategy for functionalizing porous scaffolds that show great promise as implants for tissue regeneration.     

Nanozyme-Based Supramolecular Self-Assembly As an Artificial Host Defense System For Treatment of Bacterial Infections

The proper functioning of host defense system (HDS) is the key to combating bacterial infection in biological organisms. However, the delicate HDS may be dysfunctional or dysregulated, resulting in persistent infection, tissue damage, or delayed wound healing. Herein, a powerful artificial “host defense system” (aHDS) is designed and constructed for treatment of bacterial infections. First, the aHDS can quickly trap the bacteria by electrostatic interactions. Next, the system can be stimulated to produce large amounts of cytotoxic reactive oxygen species (ROS) and exert strong antibacterial effects, which can further regulate the immune microenvironment, leading to macrophage polarization from M0 to pro-inflammatory phenotype (M1) for synergistic bacteria killing. At the later stages, the system can exhibit excellent antioxidant enzyme-like activities to reprogram the M1 macrophage to anti-inflammatory phenotype (M2) for accelerating wound healing. This powerful aHDS can effectively combat the bacteria and avoid excessive inflammatory responses for the treatment of bacteria-infected wounds.     

Macrophage Polarization Induced by Bacteria-Responsive Antibiotic-Loaded Nanozymes for Multidrug Resistance-Bacterial Infections Management

Inherited bacterial resistance and biofilm-induced local immune inactivation are important factors in the failure of antibiotics to fight against bacterial infections. Herein, antibiotic-loaded mesoporous nanozymes (HA@MRuO₂-Cip/GOx) are fabricated for overcoming bacterial resistance, and activating the local immunosuppression in biofilm microenvironment (BME). HA@MRuO₂-Cip/GOx are prepared by physical adsorption between ciprofloxacin (Cip) or glucose oxidase (GOx) and MRuO₂ NPs, and modified with hyaluronic acid (HA). In vitro, HA@MRuO₂-Cip/GOx cleaves extracellular DNA (eDNA) to disrupt biofilm, thereby enhancing Cip kill planktonic bacteria. Furthermore, HA@MRuO₂-Cip/GOx can induce polarization and enhance phagocytosis of a macrophage-derived cell line. More importantly, in vivo therapeutic performance confirms that HA@MRuO₂-Cip/GOx can trigger macrophage-related immunity, and effectively alleviate MRSA-bacterial lung infections. Accordingly, nanocatalytic therapy combined with targeted delivery of antibiotics could enhance the treatment of bacterial infections.     

Specific Chemiluminescence Imaging and Enhanced Photodynamic Therapy of Bacterial Infections by Hemin-Modified Carbon Dots

Antibacterial photodynamic therapy (aPDT) is a promising antibiotics-alternative strategy for bacterial infectious diseases, which features broad-spectrum antibacterial activity with a low risk of inducing bacterial resistance. However, clinical applications of aPDT are still hindered by the hydrophobicity-caused inadequate photodynamic activity of conventional photosensitizers and the hypoxic microenvironment of bacterial infections. To address these problems, herein, a promising strategy is developed to achieve specific chemiluminescence (CL) imaging and enhanced PDT of bacterial infections using hemin-modified carbon dots (H-CDs). The H-CDs can be facilely prepared and exhibit favorable water solubility, augmented photodynamic activity, and unique peroxidase-mimicking capacity. Compared with the free CDs, the photodynamic efficacy of H-CDs is significantly augmented due to the increased electron–hole separation efficiency. Moreover, the peroxidase catalytic performance of H-CDs enables not only infection identification via bacterial infection microenvironment-responsive CL imaging but also oxygen self-supplied aPDT with hypoxia-relief-enhanced bacteria inactivation effects. Finally, the enhanced aPDT efficiencies of H-CDs are validated in both in vivo abscess and infected wound models. This work may provide an effective antibacterial platform for the selective imaging-guided treatment of bacterial infections.     

Photo-Responded Antibacterial Therapy of Reinfection in Percutaneous Implants by Nanostructured Bio-Heterojunction

Percutaneous implants may experience infection for several times during their servicing periods. They need antibacterial activity and durability to reduce recurrent infection and cytocompatibility to reconstruct biosealing. A novel photoresponse bio-heterojunction (PCT) is developed herein. It consists of TiO₂ nanotubes loaded with CuS nanoparticles and wrapped with polydopamine (PDA) layer. In PCT, a built-in electric field directing from TiO₂ to CuS and then to PDA is formed, and with near-infrared (NIR) irradiation, it drives photoexcited electrons to transfer in opposite direction, resulting in the separation of electron–hole pairs and formation of reactive oxygen species (ROS). Simultaneously, PCT shows photothermal effect due to nonradiative relaxation of photoexcited electrons and thermal vibration of lattices. The synergic effect of photogenerated ROS and hyperthermia increases bacterial membrane permeability and leakage of cellular components, endowing PCT with outstanding antibacterial performance. More importantly, PCT has good antibacterial durability and cytocompatibility due to the inhibited leaching of CuS by PDA layer. In reinfected models, with NIR irradiation, PCT sterilizes bacteria, reduces inflammatory response and enhances re-integration of soft tissue efficiently. This work provides an outstanding bio-heterojunction for percutaneous implants in treating reinfection by NIR irradiation and rebuilding biosealing.     

A Dual‐Bioresponsive Drug‐Delivery Depot for Combination of Epigenetic Modulation and Immune Checkpoint Blockade

Patients with advanced melanoma that is of low tumor‐associated antigen (TAA) expression often respond poorly to PD‐1/PD‐L1 blockade therapy. Epigenetic modulators, such as hypomethylation agents (HMAs), can enhance the antitumor immune response by inducing TAA expression. Here, a dual bioresponsive gel depot that can respond to the acidic pH and reactive oxygen species (ROS) within the tumor microenvironment (TME) for codelivery of anti‐PD1 antibody (aPD1) and Zebularine (Zeb), an HMA, is engineered. aPD1 is first loaded into pH‐sensitive calcium carbonate nanoparticles (CaCO₃ NPs), which are then encapsulated in the ROS‐responsive hydrogel together with Zeb (Zeb‐aPD1‐NPs‐Gel). It is demonstrated that this combination therapy increases the immunogenicity of cancer cells, and also plays roles in reversing immunosuppressive TME, which contributes to inhibiting the tumor growth and prolonging the survival time of B16F10‐melanoma‐bearing mice.     

Photosensitizer‐Modified MnO2 Nanoparticles to Enhance Photodynamic Treatment of Abscesses and Boost Immune Protection for Treated Mice

The emergence of drug‐resistant bacteria and easy recurrence has been challenging in the clinical treatment of skin abscesses resulting from bacterial infections (e.g., by Staphylococcus aureus (S. aureus)). Herein, an antibacterial nanoagent capable of modulating the abscess microenvironment is designed to enhance photodynamic treatment of skin abscesses, and subsequently activate the immune system to effectively prevent abscess recurrence. In the system, manganese dioxide nanoparticles (MnO₂ NPs) with high catalytic reactivity toward H₂O₂ are modified with photosensitizer chlorine e6 (Ce6) and coated with polyethylene glycol (PEG). The obtained Ce6@MnO₂‐PEG NPs, by triggering the decomposition of lesion endogenous H₂O₂, are able to effectively relieve the hypoxic abscess microenvironment during S. aureus infection. The light‐triggered photodynamic bacterial killing effect could thus be remarkably enhanced, resulting in effective in vivo therapy of S. aureus‐induced skin abscesses. Interestingly, a notable pathogen‐specific immunological memory effect against future infection by the same species of bacteria is elicited after such treatment, owing to the release of bacterial antigens post photodynamic therapy (PDT) together with the adjuvant‐like function of manganese ions to activate the host immune system. This work thus presents a new type of photodynamic nanoagent particularly promising for highly effective light‐triggered abscess treatment and prevention of abscess recurrence.     

Mechanistic Investigation of the Biological Effects of SiO2, TiO2, and ZnO Nanoparticles on Intestinal Cells

Silicon dioxide (SiO₂), titanium dioxide (TiO₂), and zinc oxide (ZnO) are currently among the most widely used nanoparticles (NPs) in the food industry. This could potentially lead to unintended exposure of the gastrointestinal tract to these NPs. This study aims to investigate the potential side‐effects of these food‐borne NPs on intestinal cells and to mechanistically understand the observed biological responses. Among the panel of tested NPs, ZnO NPs are the most toxic. Consistently in all three tested intestinal cell models, ZnO NPs invoke the most inflammatory responses from the cells and induce the highest intracellular production of reactive oxygen species (ROS). The elevated ROS levels induce significant damage to the DNA of the cells, resulting in cell‐cycle arrest and subsequently cell death. In contrast, both SiO₂ and TiO₂ NPs elicit minimum biological responses from the intestinal cells. Overall, the study showcases the varying capability of the food‐borne NPs to induce a cellular response in the intestinal cells. In addition to physicochemical differences in the NPs, the genetic landscape of the intestinal cell models governs the toxicology profile of these food‐borne NPs.     

Peptide-Functionalized Prussian Blue Nanomaterial for Antioxidant Stress and NIR Photothermal Therapy against Alzheimer's Disease

Excessive accumulations of reactive oxygen species (ROS) and amyloid-β (Aβ) protein are closely associated with the complex pathogenesis of Alzheimer's disease (AD). Therefore, approaches that synergistically exert elimination of ROS and dissociation of Aβ fibrils are effective therapeutic strategies for correcting the AD microenvironment. Herein, a novel near infrared (NIR) responsive Prussian blue-based nanomaterial (PBK NPs) is established with excellent antioxidant activity and photothermal effect. PBK NPs possess similar activities to multiple antioxidant enzymes, including superoxide dismutase, peroxidase, and catalase, which can eliminate massive ROS and relieve oxidative stress. Under the NIR irradiation, PBK NPs can generate local heat to disaggregate Aβ fibrils efficiently. By modifying CKLVFFAED peptide, PBK NPs display obvious targeting ability for blood–brain barrier penetration and Aβ binding. Furthermore, in vivo studies demonstrate that PBK NPs have outstanding ability to decompose Aβ plaques and alleviate neuroinflammation in AD mouse model. Overall, PBK NPs provide evident neuroprotection by reducing ROS levels and regulating Aβ deposition, and may accelerate the development of multifunctional nanomaterials for delaying the progression of AD.     

Self-Assembly of Selenium-Doped Carbon Quantum Dots as Antioxidants for Hepatic Ischemia-Reperfusion Injury Management

Hepatic ischemia-reperfusion injury (HIRI) is a critical complication after liver surgery that negatively affects surgical outcomes of patients with the end-stage liver-related disease. Reactive oxygen species (ROS) are responsible for the development of ischemia-reperfusion injury and eventually lead to hepatic dysfunction. Selenium-doped carbon quantum dots (Se-CQDs) with an excellent redox-responsive property can effectively scavenge ROS and protect cells from oxidation. However, the accumulation of Se-CQDs in the liver is extremely low. To address this concern, the fabrication of Se-CQDs-lecithin nanoparticles (Se-LEC NPs) is developed through self-assembly mainly driven by the noncovalent interactions. Lecithin acting as the self-assembly building block also makes a pivotal contribution to the therapeutic performance of Se-LEC NPs due to its capability to react with ROS. The fabricated Se-LEC NPs largely accumulate in the liver, effectively scavenge ROS and inhibit the release of inflammatory cytokines, thus exerting beneficial therapeutic efficacy on HIRI. This work may open a new avenue for the design of self-assembled Se-CQDs NPs for the treatment of HIRI and other ROS-related diseases.     

HClO-Activated Fluorescence and Photosensitization from an AIE Nanoprobe for Image-Guided Bacterial Ablation in Phagocytes

Bacteria hiding in host phagocytes are difficult to kill, which can cause phagocyte disorders resulting in local and systemic tissue damage. Effective accumulation of activatable photosensitizers (PSs) in phagocytes to realize selective imaging and on-demand photodynamic ablation of bacteria is of great scientific and practical interests for precise bacteria diagnosis and treatment. Herein, HClO-activatable theranostic nanoprobes, DTF-FFP NPs, for image-guided bacterial ablation in phagocytes are introduced. DTF-FFP NPs are prepared by nanoprecipitation of an HClO-responsive near-infrared molecule FFP and an efficient PS DTF with aggregation-induced emission characteristic using an amphiphilic polymer Pluronic F127 as the encapsulation matrix. As an energy acceptor, FFP can quench both fluorescence and production of reactive oxygen species (ROS) of DTF, thus eliminating the phototoxicity of DTF-FFP NPs in normal cells and tissues. Once delivered to the infection sites, DTF-FFP NPs light up with red fluorescence and efficiently generate ROS owing to the degradation of FFP by the stimulated release of HClO in phagocytes. The selective activation of fluorescence and photosensitization is successfully confirmed by both in vitro and in vivo results, demonstrating the effectiveness and theranostic potential of DTF-FFP NPs in precise bacterial therapy.     

Collaborative Design of MgO/FeOx Nanosheets on Titanium: Combining Therapy with Regeneration

The repair of bone defects caused by osteosarcoma resection remains a clinical challenge because of the tumor recurrence and bacterial infection. Combining tumor and bacterial therapy with bone regeneration properties in bone implants is a promising strategy for the treatment of osteosarcoma. Here, a layer of MgO/FeO_x nanosheet is constructed on the Ti implant to prevent tumor recurrence and bacterial infection, while simultaneously accelerating bone formation. This MgO/FeO_x double metal oxide demonstrates good peroxidase activity to catalyze H₂O₂, which is rich in tumor microenvironment, to form reactive oxygen species (ROS), and shows good photothermal conversion capacity to produce photothermal effect, thus synergistically killing tumor cells and eliminating tumor tissue. In addition, it generates a local alkaline surface microenvironment to inhibit the energy metabolism of bacteria to enhance the photothermal antibacterial effect. Furthermore, benefiting from the generation of a Mg ion-containing alkaline microenvironment, this MgO/FeO_x film can promote the osteogenic differentiation of osteoblast and angiogenesis of vascular endothelial cells in vitro as well as accelerated bone formation in vivo. This study proposes a multifunctional platform for integrating tumor and bacterial therapy and bone regeneration, which has good application prospects for the treatment of osteosarcoma.     

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.     

Bioinspired Copper Single-Atom Catalysts for Tumor Parallel Catalytic Therapy

The oxidation of intracellular biomolecules by reactive oxygen species (ROS) forms the basis for ROS-based tumor therapy. However, the current therapeutic modalities cannot catalyze H₂O₂ and O₂ concurrently for ROS generation, thereby leading to unsatisfactory therapeutic efficacy. Herein, it is reported a bioinspired hollow N-doped carbon sphere doped with a single-atom copper species (Cu-HNCS) that can directly catalyze the decomposition of both oxygen and hydrogen peroxide to ROS, namely superoxide ion (O₂•⁻) and the hydroxyl radical (•OH), respectively, in an acidic tumor microenvironment for the oxidation of intracellular biomolecules without external energy input, thus resulting in an enhanced tumor growth inhibitory effect. Notably, the Fenton reaction turnover frequency of Cu species in Cu-HNCS is ≈5000 times higher than that of Fe in commercial Fe₃O₄ nanoparticles. Experimental results and density functional theory calculations reveal that the high catalytic activity of Cu-HNCS originates from the single-atom copper, and the calculation predicts a next-generation Fenton catalyst. This work provides an effective paradigm of tumor parallel catalytic therapy for considerably enhanced therapeutic efficacy.     

NIR-II Imaging-Guided Mitochondrial-Targeting Organic Nanoparticles for Multimodal Synergistic Tumor Therapy

Effectively interfering energy metabolism in tumor cells and simultaneously activating the in vivo immune system to perform immune attacks are meaningful for tumor treatment. However, precisely targeted therapy is still a huge challenge. Herein, a mitochondrial-targeting phototheranostic system, FE-T nanoparticles (FE-T NPs) are developed to damage mitochondria in tumor cells and change the tumor immunosuppressive microenvironment. FE-T NPs are engineered by encapsulating the near-infrared (NIR) absorbed photosensitizer IR-FE-TPP within amphiphilic copolymer DSPE-SS-PEG-COOH for high-performing with simultaneous mitochondrial-targeting, near-infrared II (NIR-II) fluorescence imaging, and synchronous photothermal therapy (PTT) /photodynamic therapy (PDT) /immune therapy (IMT). In tumor treatment, the disulfide in the copolymer can be cleaved by excess intracellular glutathione (GSH) to release IR-FE-TPP and accumulate in mitochondria. After 808 nm irradiation, the mitochondrial localization of FE-T NPs generated reactive oxygen species (ROS), and hyperthermia, leading to mitochondrial dysfunction, photoinductive apoptosis, and immunogenic cell death (ICD). Notably, in situ enhanced PDT/PTT in vivo via mitochondrial-targeting with FE-T NPs boosts highly efficient ICD toward excellent antitumor immune response. FE-T NPs provide an effective mitochondrial-targeting phototheranostic nanoplatform for imaging-guided tumor therapy.     

Polydopamine functionalized mesoporous silica as ROS-sensitive drug delivery vehicles for periodontitis treatment by modulating macrophage polarization

Periodontitis is recognized as the major cause of tooth loss in adults, posing an adverse impact on systemic health. In periodontitis, excessive production of reactive oxygen species (ROS) at the inflamed site culminates in periodontal destruction. In this study, a novel ROS-responsive drug delivery system based on polydopamine (PDA) functionalized mesoporous silica nanoparticles was developed for delivering minocycline hydrochloride (MH) to treat periodontitis. The outer PDA layer and the inner MH of the nanoparticles acted as ROS scavengers and anti-inflammatory agents, respectively. Under the synergistic action of PDA and MH, macrophages were polarized from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. The in vitro experiments provided convincing evidence that PDA could scavenge ROS effectively, and the expression of pro-inflammatory cytokines was attenuated and the secretion of anti-inflammatory cytokines was enhanced through M1 to M2 polarization of macrophages with the cooperation of MH. In addition, the results obtained from the periodontitis rat models demonstrated that the synergetic effect of PDA and MH prevented alveolar bone loss without causing any adverse effect. Taken together, the results from the present investigation provide a new strategy to remodel the inflammatory microenvironment by inducing the polarization of macrophages from M1 toward M2 state for the treatment of periodontitis.

     

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.     

Ultrafine Silver Nanoparticles Embedded in Cyclodextrin Metal‐Organic Frameworks with GRGDS Functionalization to Promote Antibacterial and Wound Healing Application

The challenge of bacterial infection increases the risk of mortality and morbidity in acute and chronic wound healing. Silver nanoparticles (Ag NPs) are a promising new version of conventional antibacterial nanosystem to fight against the bacterial resistance in concern of the drug discovery void. However, there are several challenges in controlling the size and colloidal stability of Ag NPs, which readily aggregate or coalesce in both solid and aqueous state. In this study, a template‐guided synthesis of ultrafine Ag NPs of around 2 nm using water‐soluble and biocompatible γ‐cyclodextrin metal‐organic frameworks (CD‐MOFs) is reported. The CD‐MOF based synthetic strategy integrates AgNO₃ reduction and Ag NPs immobilization in one pot achieving dual functions of reduced particle size and enhanced stability. Meanwhile, the synthesized Ag NPs are easily dispersible in aqueous media and exhibit effective bacterial inhibition. The surface modification of cross‐linked CD‐MOF particles with GRGDS peptide boosts the hemostatic effect that further enhances wound healing in synergy with the antibacterial effect. Hence, the strategy of ultrafine Ag NPs synthesis and immobilization in CD‐MOFs together with GRGDS modification holds promising potential for the rational design of effective wound healing devices.     

GSH-Depleted Nanozymes with Hyperthermia-Enhanced Dual Enzyme-Mimic Activities for Tumor Nanocatalytic Therapy

Nanocatalytic therapy, using artificial nanoscale enzyme mimics (nanozymes), is an emerging technology for therapeutic treatment of various malignant tumors. However, the relatively deficient catalytic activity of nanozymes in the tumor microenvironment (TME) restrains their biomedical applications. Here, a versatile and bacteria-like PEG/Ce-Bi@DMSN nanozyme is developed by coating uniform Bi₂S₃ nanorods (NRs) with dendritic mesoporous silica (Bi₂S₃@DMSN) and then decorating ultrasmall ceria nanozymes into the large mesopores of Bi₂S₃@DMSN. The nanozymes exhibit dual enzyme-mimic catalytic activities (peroxidase-mimic and catalase-mimic) under acidic conditions that can regulate the TME, that is, simultaneously elevate oxidative stress and relieve hypoxia. In addition, the nanozymes can effectively consume the overexpressed glutathione (GSH) through redox reaction. Photothermal therapy (PTT) is introduced to synergistically improve the dual enzyme-mimicking catalytic activities and depletion of the overexpressed GSH in the tumors by photonic hyperthermia. This is achieved by taking advantage of the desirable light absorbance in the second near-infrared (NIR-II) window of the PEG/Ce-Bi@DMSN nanozymes. Subsequently the reactive oxygen species (ROS)-mediated therapeutic efficiency is significantly improved. Therefore, this study provides a proof of concept of hyperthermia-augmented multi-enzymatic activities of nanozymes for tumor ablation.     

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.