NIR responsive scaffold with multistep shape memory and photothermal-chemodynamic properties for complex tissue defects repair and antibacterial therapy.

Complex tissue damage accompanying with bacterial infection challenges healthcare systems globally. Conventional tissue engineering scaffolds normally generate secondary implantation trauma, mismatched regeneration and infection risks. Herein, we developed an easily implanted scaffold with multistep shape memory and photothermal-chemodynamic properties to exactly match repair requirements of each part from the tissue defect by adjusting its morphology as needed meanwhile inhibiting bacterial infection on demand. Specifically, a thermal-induced shape memory scaffold was prepared using hydroxyethyl methacrylate and polyethylene glycol diacrylate, which was further combined with the photothermal agent iron tannate (FeTA) to produce NIR light-induced shape memory property. By varying ingredients ratios in each segment, this scaffold could perform a stepwise recovery under different NIR periods. This process facilitated implantation after shape fixing to avoid trauma caused by conventional methods and gradually filled irregular defects under NIR to perform suitable tissue regeneration. Moreover, FeTA also catalyzed Fenton reaction at bacterial infections with abundant H2O2, which produced excess ROS for chemodynamic antibacterial therapy. As expected, bacteriostatic rate was further enhanced by additional photothermal therapy under NIR. The in vitro and vivo results showed that our scaffold was able to perform high efficacy in both antibiosis, inflammation reduction and wound healing acceleration, indicating a promising candidate for the regeneration of complex tissue damage with bacterial infection.

An iron-based metal-organic framework nanoplatform for enhanced ferroptosis and oridonin delivery as a comprehensive antitumor strategy.

Ferroptosis is a recently discovered pathway for regulated cell death pathway. However, its efficacy is affected by limited iron content and intracellular ion homeostasis. Here, we designed a metal-organic framework (MOF)-based nanoplatform that incorporates calcium peroxide (CaO2) and oridonin (ORI). This platform can improve the tumor microenvironment and disrupt intracellular iron homeostasis, thereby enhancing ferroptosis therapy. Fused cell membranes (FM) were used to modify nanoparticles (ORI@CaO2@Fe-TCPP, NPs) to produce FM@ORI@CaO2@Fe-TCPP (FM@NPs). The encapsulated ORI inhibited the HSPB1/PCBP1/IREB2 and FSP1/COQ10 pathways simultaneously, working in tandem with Fe3+ to induce ferroptosis. Photodynamic therapy (PDT) guided by porphyrin (TCPP) significantly enhanced ferroptosis through excessive accumulation of reactive oxygen species (ROS). This self-amplifying strategy promoted robust ferroptosis, which could work synergistically with FM-mediated immunotherapy. In vivo experiments showed that FM@NPs inhibited 91.57% of melanoma cells within six days, a rate 5.6 times higher than chemotherapy alone. FM@NPs were biodegraded and directly eliminated in the urine or faeces without substantial toxicity. Thus, this study demonstrated that combining immunotherapy with efficient ferroptosis induction through nanotechnology is a feasible and promising strategy for melanoma treatment.

Photothermal and enhanced chemodynamic reinforced anti-tumor therapy based on PDA@POM nanocomposites.

Chemodynamic therapy (CDT) and photothermal therapy (PTT) have both demonstrated considerable efficacy in the tumor treatment individually, owing to their non-invasive nature and excellent selectivity. However, due to the propensity of tumors for metastasis and recurrence, a singular therapeutic approach falls short of achieving optimal treatment outcomes. Polydopamine (PDA) has excellent photothermal conversion ability and polyoxometalates (POMs) possess diverse enzymatic activities. Here, we synthesized PDA@POM nanospheres comprising polydopamine-coated Tungsten-based polyoxometalate (W-POM). These nanospheres leverage dual enzymatic activities that synergistically enhance both chemodynamic and photothermal therapies for tumor treatment. The PDA-mediated PTT effect enables precise tumor cell destruction, while the W-POM nanozymes catalyzes the generation of highly toxic reactive oxygen species (ROS) from hydrogen peroxide within tumor cells through a Fenton-like reaction, which mitigates tumor hypoxia and induces tumor cell death. This synergistic photothermal catalytic therapy shows enhanced efficacy in tumor suppression, providing a promising new approach for tumor treatment.

Tumor Microenvironment-Responsive Magnetotactic Bacteria-Based Multi-Drug Delivery Platform for MRI-Visualized Tumor Photothermal Chemodynamic Therapy.

Cancer cells display elevated reactive oxygen species (ROS) and altered redox status. Herein, based on these characteristics, we present a multi-drug delivery platform, AMB@PDAP-Fe (APPF), from the magnetotactic bacterium AMB-1 and realize MRI-visualized tumor-microenvironment-responsive photothermal-chemodynamic therapy. The Fe3+ in PDAP-Fe is reduced by the GSH at the tumor site and is released in the form of highly active Fe2+, which catalyzes the generation of ROS through the Fenton reaction and inhibits tumor growth. At the same time, the significant absorption of the mineralized magnetosomes in AMB-1 cells in the NIR region enables them to efficiently convert near-infrared light into heat energy for photothermal therapy (PTT), to which PDAP also contributes. The heat generated in the PTT process accelerates the process of Fe2+ release, thereby achieving an enhanced Fenton reaction in the tumor microenvironment. In addition, the magnetosomes in AMB-1 are used as an MRI contrast agent, and the curing process is visualized. This tumor microenvironment-responsive MTB-based multi-drug delivery platform displays the potency to combat tumors and demonstrates the utility and practicality of understanding the cooperative molecular mechanism when designing multi-drug combination therapies.

Polyphenol-hyaluronic acid-based hydrogel remodels the wound microenvironment and eliminates bacterial infection for accelerating wound healing.

The wound microenvironment, often characterized by alkaline pH and severe hypoxia, presents significant challenges to the healing of bacterial-infected wounds. While considerable research has focused on improving wound healing through effective bacterial elimination using advanced therapeutic approaches, the importance of regulating the wound microenvironment has received less emphasis. In this work, we developed a biocompatible hydrogel, HTFC, by incorporating CaO2 nanoparticles (CaO2 NPs) into a gel formed by tannic acid (TA), hyaluronic acid (HA), and Fe3+. The HA and TA in HTFC hydrogel help to create a slightly acidic microenvironment, facilitating the decomposition of CaO2 NPs to release H2O2 for chemodynamic therapy (CDT). The reduction properties of TA promote the recycling of Fe3+/Fe2+, enhancing CDT efficacy and partially converting H2O2 to O2, thereby alleviating hypoxia. Additionally, FeIIITA complexes in HTFC enhance CDT through photothermal therapy (PTT)-induced improvement of the Fenton reaction. This multifunctional hydrogel, with its synergistic effects of PTT and CDT, along with its ability to remodel the wound microenvironment from hypoxic and alkaline to normoxic and acidic, accelerates the bacterial-infected wound healing process.

Autophagic cell death induced by pH modulation for enhanced iron-based chemodynamic therapy.

Iron-based chemodynamic therapy (CDT) exhibits commendable biocompatibility and selectivity, but its efficacy is constrained by the intracellular pH of tumors. To overcome this obstacle, we constructed a silica delivery platform loaded with autophagy-inducing reagents (rapamycin, RAPA) and iron-based Fenton reagents (Fe3O4). This platform was utilized to explore a novel strategy that leverages autophagy to decrease tumor acidity, consequently boosting the effectiveness of CDT. Both in vitro and in vivo experiments revealed that RAPA prompted the generation of acidic organelles (e.g., autophagic vacuoles and autophagosomes), effectively changing the intracellular pH in the tumor microenvironment. Furthermore, RAPA-induced tumor acidification significantly amplified the efficacy of Fe3O4-based Fenton reactions, consequently increasing the effectiveness of Fe3O4-based CDT. This innovative approach, which leverages the interplay between autophagy induction and iron-based CDT, shows promise in overcoming the limitations posed by tumor pH, thus offering a more efficient approach to tumor treatments.

Metal-phenolic network crosslinked nanogel with prolonged biofilm retention for dihydroartemisinin/NIR synergistically enhanced chemodynamic therapy.

Chemodynamic therapy (CDT) is emerging as a promising treatment for biofilm infections. However, its effectiveness is significantly hindered by several factors: the body's stable temperature, a limited supply of Fe2+ ions, and inadequate endogenous levels of H2O2 at the infection sites. Herin, our study introduces MPN-crosslinked hyaluronic acid (HA) nanogels as an effective strategy for treating biofilm-associated infections. The DHA@HA-TA/Fe (DHTF) nanogel is synthesized through the coordination reaction between Fe2+ ions and tannic acid (TA)-modified HA, with dihydroartemisinin (DHA) encapsulated within the structure. DHTF exhibits pH-/hyaluronidase-responsiveness in the biofilm infection microenvironment, enabling sustained release of DHA as a substitute for H2O2 and Fe2+ for CDT. The incorporation of Fe2+/TA-based MPN and DHA within the nanogels enables photothermal/DHA dually-enhanced CDT, facilitating efficient disruption of biofilm matrices and bacterial eradication through boosting reactive oxygen species production. In vivo studies demonstrate that DHTF exhibit prolonged retention within biofilms. This ensures a sustained release of therapeutic agents and continuous anti-biofilm activity. Eventually, both in vitro and in vivo evaluations consistently confirm the significant anti-biofilm capacity of DHTF. Our findings highlight the potential of DHTF as a promising nanomedicine for biofilm-related infections, offering efficient treatment strategies that could improve clinical management of these challenging conditions.

Biomimetic Copper-Containing Nanogels for Imaging-Guided Tumor Chemo-Chemodynamic-Immunotherapy.

Developing multifunctional nanoplatforms to comprehensively modulate the tumor microenvironment and enhance diagnostic and therapeutic outcomes still remains a great challenge. Here, we report the facile construction of a multivariate nanoplatform based on cancer cell membrane (CM)-encapsulated redox-responsive poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) co-loaded with Cu(II) and chemotherapeutic drug toyocamycin (Toy) for magnetic resonance (MR) imaging-guided combination tumor chemodynamic therapy/chemoimmunotherapy. We show that redox-responsive PVCL NGs formed through precipitation polymerization can be aminated, conjugated with 3,4-dihydroxyhydrocinnamic acid for Cu(II) complexation, physically loaded with Toy, and finally camouflaged with CMs. The created ADCT@CM NGs with an average size of 113.0 nm are stable under physiological conditions and can efficiently release Cu(II) and Toy under tumor microenvironment with a high level of glutathione. Meanwhile, the developed NGs are able to enhance cancer cell oxidative stress and endoplasmic reticulum stress by synergizing the effects of chemodynamic therapy mediated by Cu-based Fenton-like reaction and Toy-mediated chemotherapy, thereby triggering significant immunogenic cell death (ICD). In a melanoma mouse model, the NGs show potent immune activation effects to reinforce tumor therapeutic efficacy through ICD induction and immune modulation including high levels of immune cytokine secretion, increased tumor infiltration of CD8+ cytotoxic T cells, and reduced tumor infiltration of regulatory T cells. With the CM coating and Cu(II) loading, the developed NG platform demonstrates homologous tumor targeting and T1-weighted MR imaging, hence providing a general biomimetic NG platform for ICD-facilitated tumor theranostic nanoplatform. STATEMENT OF SIGNIFICANCE: Developing multifunctional nanoplatforms to comprehensively modulate the tumor microenvironment (TME) and enhance theranostic outcomes remains a challenge. Here, a cancer cell membrane (CM)-camouflaged nanoplatform based on aminated poly(N-vinylcaprolactam) nanogels (NGs) co-loaded with Cu(II) and toyocamycin (Toy) was prepared for magnetic resonance (MR) imaging-guided combination tumor chemodynamic therapy/chemoimmunotherapy. The tumor targeting specificity and efficient TME-triggered release of Cu(II) and Toy could enhance tumor cell oxidative stress and endoplasmic reticulum stress by synergizing the effects of chemodynamic therapy mediated by Cu-based Fenton-like reaction and Toy-mediated chemotherapy, respectively, thereby leading to significant immunogenic cell death (ICD) and immune response. With the CM coating and Cu(II) loading, the developed NG platform also demonstrates good T1-weighted tumor MR imaging performance. Hence, this study provides a general biomimetic NG platform for ICD-facilitated tumor theranostics.

Multifunctional EGCG@ZIF-8 Nanoplatform with Photodynamic Therapy/Chemodynamic Therapy Antibacterial Properties Promotes Infected Wound Healing.

Damaged skin is susceptible to invasion by harmful microorganisms, especially Staphylococcus aureus and Escherichia coli, which can delay healing. Epigallocatechin-3-gallate (EGCG) is a natural compound known for effectively promoting wound healing and its potent anti-inflammatory effects. However, its application is limited due to its susceptibility to oxidation and isomerization, which alter its structure. The use of zeolitic imidazolate framework-8 (ZIF-8) can effectively tackle these issues. This study introduces an oxygen (O2) and hydrogen peroxide (H2O2) self-supplying ZIF-8 nanoplatform designed to enhance the bioavailability of EGCG, combining photodynamic therapy (PDT) and chemodynamic therapy (CDT) to improve antibacterial properties and ultimately accelerate wound healing. For this purpose, EGCG and indocyanine green (ICG), a photosensitizer, were successively integrated into a ZIF-8, and coated with bovine serum albumin (BSA) to enhance biocompatibility. The outer layer of this construct was further modified with manganese dioxide (MnO2) to promote CDT and calcium peroxide (CaO2) to supply H2O2 and O2, resulting in the final nanoplatform EGCG-ICG@ZIF-8/BSA-MnO2/CaO2 (EIZBMC). In in vitro experiments under 808 nm laser, EIZBMC exhibited synergistic antibacterial effects through PDT and CDT. This combination effectively released reactive oxygen species (ROS), which mediated oxidative stress to inhibit the bacteria. Subsequently, in a murine model of wound infection, EIZBMC not only exerted antibacterial effects through PDT and CDT but also alleviated the inflammatory condition and promoted the regeneration of collagen fibers, which led to accelerated wound healing. Overall, this research presents a promising approach to enhancing the therapeutic efficacy of EGCG by leveraging the synergistic antibacterial effects of PDT and CDT. This multifunctional nanoplatform maximizes EGCG's anti-inflammatory properties, offering a potent solution for promoting infected wound healing.

Molecular Photoswitching Unlocks Glucose Oxidase for Synergistically Reinforcing Fenton Reactions for Antitumor Chemodynamic Therapy.

We have developed a new type of nanoparticles with potent antitumor activity photoactivatable via the combination of molecular photoswitching of spiropyran (SP) and enzymatic reaction of glucose oxidase (GOx). As two key processes involved therein, Fe(III)-to-Fe(II) photoreduction in Fe(III) metal-organic frameworks (MOFs) brings about the release of free Fe2+/Fe3+ while the photoswitching of SP to merocyanine (MC) unlocks the enzymatic activity of GOx that was pre-passivated by SP. The release of free Fe3+ boosts its hydrolysis and therefore enables the acidification of microenvironment, which is further reinforced by one of the products of the GOx-mediated glucose oxidation reaction, gluconic acid (GlcA). Based on the generation of Fe2+ and acidic milieu together with another product of the oxidation reaction, hydrogen peroxide (H2O2), these two processes jointly present triple enabling factors for generating lethal hydroxyl radicals (•OH) species via Fenton reactions and therefore oxidative stress capable of inhibiting tumor. The antitumor potency of such nanoparticle is verified in tumor-bearing model mice in vivo, proclaiming its potential as a potent and safe agent based on the unique mechanism of optically manipulating enzyme activity for synergistic antitumor therapeutics with high spatial precision, enhanced efficacy and minimized side effects.

Engineering Two-dimensional tungsten-doped molybdenum selenide transformed conformational nanoarchitectonics: Trimodal therapeutic nanoagents for enhanced synergistic Photothermal/Chemodynamic/Chemotherapy of breast carcinoma.

Two-dimensional transition metal dichalcogenides (TMDCs) exhibit promising photothermal therapy (PTT) and chemodynamic therapy (CDT) for anti-tumour treatment. Herein, we proposed an engineering strategy to regulate the lattice structure of tungsten-doped molybdenum selenide (MoxW1-xSe2) transformed conformational nanoarchitectonics using a microwave-assisted solvothermal method for enhancing peroxidase (POD)-like catalytic performance by adjusting the ratio of molybdenum (Mo) and tungsten (W). Furthermore, the optimised Mo0.8W0.2Se2 nanoflakes surface was modified with chitosan (CHI) for improved biocompatibility and nanocatalytic efficacy, then the obtained CHI-Mo0.8W0.2Se2 subsequently loaded the chemotherapeutic drug mitoxantrone (MTO) for enhanced 4 T1 cells killing ability, shortly denoted as CHI-Mo0.8W0.2Se2-MTO for PTT-augmented CDT and chemotherapy (CT). A series of performance validations successfully showed that electrons tend to transfer from W to Mo in CHI-Mo0.8W0.2Se2, which resulted in superior POD-like activity (Km = 0.038 mM) of CHI-Mo0.8W0.2Se2 compared with that of horseradish peroxidase. Furthermore, CHI-Mo0.8W0.2Se2-MTO with excellent photothermal conversion efficiency (PCE=63.2 %) in the near-infrared (NIR) region could further promote endogenous •OH generation and MTO controlled release within solid tumours. In vivo studies confirmed the successful achievement of synergistic therapeutic effects (tumour inhibition rate of over 90 %) with minimised side effects. Versatile therapeutic nanoagents hold great potential for personalised therapy of breast cancer and will find their way to the pharmaceutical field.

Tumor Microenvironment-Activated In Situ Synthesis of Peroxynitrite for Enhanced Chemodynamic Therapy.

Chemodynamic therapy (CDT) can induce cancer cell death through hydroxyl radicals (·OH) generated from Fenton or Fenton-like reactions. Compared with traditional therapies, CDT effectively overcomes inevitable drug resistance and exhibits low side effects. However, clinical application still faces challenges, primarily due to insufficient ·OH generation and the short-lifetime of ·OH in vivo. To address these challenges, we developed a peroxynitrite (ONOO-)-based CDT nanodrug (DOX@PMOF) composed of MOF-199, NO donor (PArg), and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) activator (doxorubicin, DOX). In DOX@PMOF, MOF-199 serves as both a carrier for loading DOX and a source of Cu+ for triggering CDT. Upon uptake by cancer cells, the high concentration of glutathione (GSH) reduces MOF-199 to Cu+, which then reacts with H2O2 to generate ·OH. Moreover, the released DOX upregulates NOX4 expression, leading to the elevated H2O2 level and thereby promoting a high-efficiency Fenton-like reaction for sufficient ·OH generation. Subsequently, PArg generates abundant NO in response to the tumor microenvironment, leading to a cascade of NO and ·OH for the in situ synthesis of ONOO-. ONOO- is more toxic and has a longer lifetime and diffusion distance than ·OH, resulting in a more effective CDT treatment. To further enhance the in vivo therapeutic effect, we coated DOX@PMOF with a homologous cell membrane to form an active tumor-targeting nanodrug (DOX@MPMOF), which has demonstrated the ability to effectively inhibit tumor growth and metastasis while exhibiting good biosafety.

Novel strategies of glutathione depletion in photodynamic and chemodynamic therapy: A review.

Cancer remains a health problem worldwide; therefore, developing new therapies to increase the effectiveness of anticancer treatments is necessary. Two such methods are photodynamic therapy (PDT) and chemodynamic therapy (CDT). The intensive growth and increased metabolism of tumors lead to elevated levels of reactive oxygen species (ROS) within cancer cells. These cells develop several antioxidant mechanisms to protect them from this oxidative stress. Antioxidants also make tumors more resistant to chemotherapy and radiation. Glutathione (GSH) is an important and the most abundant endogenous cellular antioxidant. Photodynamic therapy and CDT are new methods that are based on the production of ROS,­ therefore increasing oxidative stress in cancer cells. A significant problem with these therapies is the increased GSH levels, which is an adaptation of cancer cells to augmented metabolic processes. This paper presents various GSH depletion strategies that are used to improve PDT and CDT. While the main goal of GSH depletion in both PDT and CDT is to prevent its interaction with the ROS generated by these therapies, it should be remembered that the reduction of its level itself may initiate pathways leading to cancer cell death.

Iron-based magnetic nanocomplexes for combined chemodynamic and photothermal cancer therapy through enhanced ferroptosis.

Chemodynamic therapy (CDT) guided by Fenton chemistry and iron-containing materials can induce ferroptosis as a prospective cancer treatment method, but the inefficient Fe3+/Fe2+ conversion restricts the monotherapeutic performances. Here, an iron-based nanoplatform (Fe3O4-SRF@FeTA) including a magnetic core and a reductive film is developed for combined CDT and photothermal therapy (PTT) through ferroptosis augmentation. The inner iron oxide core serves as a photothermal transducer, a magnet-responsive module, and an iron reservoir for CDT. The coated Fe3+-tannic acid film (FeTA) provides extra iron and reductants for Fe3+/Fe2+ conversion acceleration, and functions as a door keeper for the pH- and light-responsive release of the embedded ferroptosis inducer sorafenib (SRF). The in vitro results demonstrate that the iron-based nanocomplexes promote the production of lipid peroxide through the amplified Fenton activity, and downregulate glutathione involved in lipid peroxide repair system through the responsively released SRF. Upon accumulation in tumor by magnetic targeting and sequential laser irradiation locoregionally, Fe3O4-SRF@FeTA nanocomplexes present prominent in vivo anticancer efficacy by leveraging PTT and CDT-enhanced ferroptosis.

Metal-organic cage as a theranostic nanoplatform for magnetic resonance imaging guided chemodynamic therapy.

Rationale: Theranostic nanoplatforms exert a vital role in facilitating concurrent real-time diagnosis and on-demand treatment of diseases, thereby making contributions to the improvement of therapeutic efficacy. Nevertheless, the structural intricacy and the absence of well-defined integration of dual functionality persist as challenges in the development of theranostic nanoplatforms. Methods: We develop an atomically precise theranostic nanoplatform based on metal-organic cage (MOC) to provide magnetic resonance imaging (MRI) guided chemodynamic therapy (CDT) for cancer therapy and assess the theranostic performance both in vitro and in vivo. Through UV-vis spectroscopy, electron paramagnetic resonance (EPR), confocal microscopy, flow cytometry, immunofluorescence staining, and western blotting, the ability of MOC-Mn to generate •OH and the subsequent inhibition of HeLa cells was confirmed. Results: The MOC-Mn composed of manganese and calixarene was successfully synthesized and comprehensively characterized. The catalytic activity of manganese within MOC-Mn facilitated the efficient generation of hydroxyl radicals (•OH) through a Fenton-like reaction, leveraging the high concentrations of hydrogen peroxide in the tumor microenvironment (TME). Additionally, its capacity to prolong the T1 relaxation time and augment the MR signal was observed. The theranostic efficacy was verified via rigorous in vitro and in vivo experiments, indicating that MOC-Mn offered clearer visualization of tumor particulars and substantial suppression of tumor growth. Conclusion: This study showcases a precise MRI-guided CDT theranostic nanoplatform for cancer therapy, thereby promoting the advancement of precise nanomedicine and structure-function research.

Rational design of Au-Bi bimetallic nanozyme for NIR-II laser mediated multifunctional combined tumor therapy.

To maximize the therapeutic effects and minimize the adverse effects of synergistic tumor therapies, a multifunctional nanozyme Au-Bi/ZIF-8@DOX@HA (ABZ@DOX@HA) was designed and synthesized through the Au and Bi bimetallic doping of ZIF-8, loading of the DOX, and modifying with hyaluronic acid (HA). The ABZ@DOX@HA nanoparticles (NPs) could simulate the enzymatic activities of glucose oxidase (GOx) and peroxidase (POD). Upon irradiated by near-infrared region (NIR-II) laser, the strong synergism of the photothermal abilities of the loaded Au and Bi nanodots accelerated the collapse of the ABZ structure at the tumor site considerably and released Au, Bi nanodots and DOX. The results in vitro and in vivo proved that ABZ@DOX@HA nanozyme could effectively exert the combined tumor therapy of starvation treatment, photothermal therapy (PTT), chemodynamic therapy (CDT) and chemotherapy. The current research provides a new strategy to address the inherent challenges of easy clearance and short blood circulation of small-sized NPs during the treatment of tumors with nanomedicine, as well as the aggregation and oxidation of inorganic nanodots.

Rationally designed catalytic nanoplatform for enhanced chemoimmunotherapy via deploying endogenous plus exogenous copper and remodeling tumor microenvironment.

Chemodynamic therapy represents a novel tumor therapeutic modality via triggering catalytic reactions in tumors to yield highly toxic reactive oxygen species (ROS). Nevertheless, low efficiency catalytic ability, potential systemic toxicity and inefficient tumor targeting, have hindered the efficacy of chemodynamic therapy. Herein, a rationally designed catalytic nanoplatform, composed of folate acid conjugated liposomes loaded with copper peroxide (CP) and chloroquine (CQ; a clinical drug) (denoted as CC@LPF), could power maximal tumor cytotoxicity, mechanistically via maneuvering endogenous and exogenous copper for a highly efficient catalytic reaction. Despite a massive autophagosome accumulation elicited by CP-powered autophagic initiation and CQ-induced autolysosomal blockage, the robust ROS, but not aberrant autophagy, underlies the synergistic tumor inhibition. Otherwise, this combined mode also elicits an early onset, above all, long-term high-level existence of immunogenic cell death markers, associated with ROS and aberrant autophagy -triggered endoplasmic reticulum stress. Besides, CC@LPF, with tumor targeting capability and selective tumor cytotoxicity, could elicit intratumor dendritic cells (mainly attributed to CQ) and tumor infiltrating CD8+ T cells, upon combining with PD-L1 therapeutic antibody, further induce significant anti-tumor effect. Collectively, the rationally designed nanoplatform, CC@LPF, could enhance tumor chemoimmunotherapy via deploying endogenous plus exogenous copper and remodeling tumor microenvironment.

Hyaluronic acid-covered ferric ion-rich nanobullets with high zoledronic acid payload for breast tumor-targeted chemo/chemodynamic therapy.

Due to the heterogeneity of the tumor microenvironment, the clinical efficacy of tumor treatment is not satisfied, highlighting the necessity for new strategies to tackle this issue. To effectively treat breast tumors by tumor-targeted chemo/chemodynamic therapy, herein, the Fe3+-rich MIL-88B nanobullets (MNs) covered with hyaluronic acid (HA) were fabricated as vehicles of zoledronic acid (ZA). The attained ZA@HMNs showed a high ZA payload (ca 29.6 %), outstanding colloidal stability in the serum-containing milieu, and accelerated ZA as well as Fe3+ release under weakly acidic and glutathione (GSH)-rich conditions. Also, the ZA@HMNs consumed GSH by GSH-mediated Fe3+ reduction and converted H2O2 into OH via Fenton or Fenton-like reaction with pH reduction. After being internalized by 4T1 cells upon CD44-mediated endocytosis, the ZA@HMNs depleted intracellular GSH and degraded H2O2 into OH, thus eliciting lipid peroxidation and mitochondria damage to suppress cell proliferation. Also, the ZA@HMNs remarkably killed macrophage-like RAW 264.7 cells. Importantly, the in vivo studies and ki67 and GPX4 staining of tumor sections demonstrated that the ZA@HMNs efficiently accumulated in 4T1 tumors to hinder tumor growth via ZA chemotherapy combined with OH-mediated ferroptosis. This work presents a practicable strategy to fabricate ZA@HMNs for breast tumor-targeted chemo/chemodynamic therapy with potential clinical translation.

CoNiCoNC tumor therapy by two-ways producing H2O2 to aggravate energy metabolism, chemokinetics, and ferroptosis.

The effectiveness of chemokinetic therapy nanozymes is severely constrained because of the low H2O2 levels in the tumor microenvironment. Unlike other self-produced H2O2 nanozymes, the N-CNTs-encapsulated CoNi alloy (CoNiCoNC) with glucose oxidase and lactate oxidase activities has two ways to produce H2O2. It can facilitate the transformation of glucose and lactic acid into H2O2 simultaneously. First, the H2O2 generation pathway is favorable for aggravating energy metabolism. Second, some produced H2O2 can be decomposed by CoNiCoNC to H2O and O2 with the 4e- pathway to alleviate the TME hypoxia. Third, H2O2 can be catalyzed to form OH to enhance reactive oxygen species (ROS) content. Through proteomic analysis, nanozymes substantially impact the metabolic pathways of cancer cells because of their aggravating energy metabolism. The high levels of ROS can cause mitochondrial lipid peroxidation and cellular ferroptosis. Consequently, the two-way H2O2-selective nanoenzymatic platform realizes the synergistic effect of starvation therapy and chemokinetics.

X-ray triggered scintillator versatile nanocatalytic platform for synergistic photodynamic/chemodynamic therapy.

Nanocatalysts with photodynamic therapy (PDT) and chemodynamic therapy (CDT) are excellent for tumor therapy. However, it is still challenging to achieve complete tumor eradication due to the drawbacks of limited penetration depth of intratumoural tissues, hypoxia and complexity of the tumor microenvironment (TME). Herein, we fabricated an integrated multifunctional nanoreactor (LuAG:Tb/Ce-RB@ZIF-8-Au2Pt-HA, LRZAPH) combining scintillating nanoparticles (SCNPs, LuAG:Tb/Ce), a metal-organic framework (ZIF-8), and bimetallic Au2Pt for X-ray-triggered PDT and dual noble-metal nanozyme catalyzed CDT. Such a nanoreactor not only significantly enhanced the PDT effect under X-ray irradiation through full resonance energy transfer from LuAG:Tb/Ce scintillator to Ross Bengal (RB), but also facilitated the reactive oxygen species (ROS) and oxygen (O2) production through the excellent peroxidase-like (POD-like) and catalase-like (CAT-like) catalytic properties of Au2Pt nanozymes. O2 also alleviates hypoxia in intratumoural tissues during coordinated PDT. In addition, the dissociation behavior of ZIF-8 with pH-responsive and targeted of hyaluronic acid (HA) in acidic TME significantly enhanced the therapeutic efficacy of LRZAPH nanocatalysts. Significantly, the high tumor growth inhibition rate of 93 % was revealed due to radiotherapy (RT)/PDT/CDT synergetic therapy in vivo, which minimized the toxic and side effects of conventional clinical radiotherapy/chemotherapy on human. The synergistic effect of LRZAPH nanocatalysts on PDT and catalytically induced CDT is expected to provide new pathways for effective treatment of deep tumors.