Hypoxia Relief Research Articles

Dual-action nanoplatform with a synergetic strategy to promote oxygen accumulation for enhanced photodynamic therapy against hypoxic tumors

With the development of redox-related therapy modalities in cancer therapy, photodynamic therapy (PDT) has gradually become the most widely used type in the clinic. However, the hypoxic tumor microenvironment restricted the curative effect of PDT. Here, a strategic hypoxia relief nanodrug delivery system (SHRN) with a synergetic strategy was designed to alleviate tumor hypoxia on the basis of PDT. Specifically, the oxygen producer MnO2, oxygen consumption inhibitor atovaquone (ATO) and photosensitizer hypericin (HY) were loaded in SHRN. MnO2 reacted with excess H2O2 in the tumor microenvironment to increase oxygen generation, while ATO inhibited electron transfer in the aerobic respiratory chain to decrease oxygen consumption. Then, HY utilized this sufficient oxygen to produce ROS under irradiation to enhance the PDT effect. In vitro and in vivo assays confirmed that SHRN exhibits powerful and overall antitumor PDT effects. This formulation may provide an alternative strategy for the development of PDT effects in hypoxic tumor microenvironments. Statement of significanceWe constructed a strategic hypoxia relief nanodrug delivery system (SHRN) with a synergetic strategy to alleviate tumor hypoxia on the basis of photodynamic therapy (PDT). This work uniquely aimed at not only increased O2 generation in hypoxic tumor microenvironment but also reduced O2 consumption. Moreover, we designed a nanodrug delivery system to enhance the tumor permeability of SHRN. In vitro and in vivo assays all confirmed that SHRN exhibited powerful and overall antitumor effects. This formulation may provide an alternative strategy for the development of the PDT effect in hypoxic solid tumor.

Tumor microenvironment-responsive nanohybrid for hypoxia amelioration with photodynamic and near-infrared II photothermal combination therapy

Phototherapy, particularly photothermal therapy (PTT) and photodynamic therapy (PDT), has been widely investigated for tumor treatment. However, the limited tissue penetration depth of light in the near-infrared I (NIR-I) region and the hypoxic tumor microenvironment (TME) severely constrain their clinical applications. To address these challenges, in the present study, we developed a chlorin e6 (Ce6) and MnO2-coloaded, hyaluronic acid (HA)-coated single-walled carbon nanohorns (SWNHs) nanohybrid (HA-Ce6-MnO2@SWNHs) for PDT and PTT combination therapy of tumor. HA-Ce6-MnO2@SWNHs responded to the mild acidic TME to ameliorate tumor hypoxia, thus enhancing tumor PDT. Moreover, HA-Ce6-MnO2@SWNHs had a high photothermal conversion efficiency at 1064 nm (55.48%), which enabled deep tissue penetration (3.05 cm) and allowed for highly efficient tumor PTT in near-infrared II (NIR-II) window. PDT and PTT combination therapy with HA-Ce6-MnO2@SWNHs achieved a good therapeutic efficacy on 4T1 tumor-bearing mice, eradicating the primary tumors and suppressing cancer recurrence. Our study provides a promising strategy for developing a hypoxia relief and deep tissue penetration phototherapy platform by using SWNHs for highly effective tumor PDT and NIR-II PTT combination therapy. Statement of SignificanceThe hypoxic tumor microenvironment (TME) and the limited penetration of the NIR-I light in biological tissues compromise the efficacy of photothermal therapy (PTT) and photodynamic therapy (PDT) on tumors. Here, we developed a chlorin e6 (Ce6) and MnO2-coloaded, hyaluronic acid (HA)-coated single-walled carbon nanohorns (SWNHs) nanohybrid (HA-Ce6-MnO2@SWNHs) for PDT and PTT combination therapy of tumors. The nanohybrid could efficiently accumulate in tumors through CD44-mediated active targeting. The sequential MnO2-enhanced PDT and efficient NIR-II PTT had a remarkable therapeutic effect by eliminating the primary tumor and simultaneously inhibiting tumor recurrence.

Biomimetic ZIF8 Nanosystem With Tumor Hypoxia Relief Ability to Enhance Chemo-Photothermal Synergistic Therapy.

Tumor hypoxic microenvironment can reduce the therapeutic effects of chemotherapy, radiotherapy, photodynamic therapy, immunotherapy, etc. It is also a potential source of tumor recurrence and metastasis. A biomimetic nanosystem based on zeolitic imidazolate framework 8 (ZIF8), which had multifunctions of hypoxia relief, chemotherapy, and photothermal therapy, was established to improve tumor hypoxic microenvironment and overcome the corresponding therapeutic resistance. ZIF8 enveloped with DOX and CuS nanoparticles (DC@ZIF8) was synthesized by a sedimentation method. Red blood cell membrane and catalase (CAT) were coated onto DC@ZIF8 and biomimetic nanosystem (DC@ZIF8-MEMC) was formed. The designed DC@ZIF8-MEMC had a shape of polyhedron with an average particle size around 254 nm. The loading content of DOX, CAT, and CuS was 4.9%, 6.2%, and 2.5%, separately. The release of DOX from DC@ZIF8-MEMC was pH dependent and significantly faster at pH 5 due to the degradation of ZIF8. DC@ZIF8-MEMC exhibited outstanding photothermal conversion properties and excellent antitumor effect in vitro and in vivo. Moreover, the hypoxia relief by CAT was proved to have good sensitization effect on chemo-photothermal combined therapy. DC@ZIF8-MEMC is a prospective nanosystem, which can realize great chemo-photothermal synergistic antitumor effect under the sensitization of CAT. The biomimetic multifunctional nanoplatform provides a potential strategy of chemo-photothermal synergistic antitumor effect under the sensitization of CAT.

Surface engineered iron oxide nanozyme for synergistic chemodynamic/photodynamic therapy with glutathione depletion and hypoxia relief

Reactive oxygen species (ROS)-based therapies, such as photodynamic therapy (PDT) and chemodynamic therapy (CDT), hold great promise to cancer treatment. However, their efficacies are subject to hypoxia and overexpressed glutathione (GSH) in tumor microenvironment (TME). Herein, we develop Mn (II) ions and pyropheophorbide (PPa) engineered iron oxide nanoparticles (IMOP) to regulate tumor hypoxia and deplete GSH for synergistic CDT/PDT. In the TME, IMOP could catalytically decompose hydrogen peroxide (H2O2) to hydroxyl radicals (·OH) as a CDT agent. Significantly, IMOP exhibits high catalase-like and glutathione peroxidase-like activities simultaneously. Once enriching into tumor, IMOP could catalyze H2O2 to oxygen (O2) to overcome hypoxic TME for improved 1O2 generation via PPa-mediated PDT. Meanwhile, the glutathione peroxidase-like activity ensure IMO to reduce the intratumoral GSH concentration and further reduce the consumption of active ROS during therapy. We demonstrated that the regulation by IMOP elicited synergistic CDT/PDT efficacy for enhanced ROS-based cancer treatment both in vitro and in vivo. Moreover, the existence of Mn (II) allowed IMO with T1 contrast behavior to monitor the progress of CDT/PDT in magnetic resonance imaging. This work provides a new guidance for designing TME-based anticancer platform for effective and precise cancer treatment.

Light amplified oxidative stress in tumor microenvironment by carbonized hemin nanoparticles for boosting photodynamic anticancer therapy

Photodynamic therapy (PDT), which utilizes light excite photosensitizers (PSs) to generate reactive oxygen species (ROS) and consequently ablate cancer cells or diseased tissue, has attracted a great deal of attention in the last decades due to its unique advantages. However, the advancement of PDT is restricted by the inherent characteristics of PS and tumor microenvironment (TME). It is urgent to explore high-performance PSs with TME regulation capability and subsequently improve the therapeutic outcomes. Herein, we reported a newly engineered PS of polymer encapsulated carbonized hemin nanoparticles (P-CHNPs) via a facile synthesis procedure for boosting photodynamic anticancer therapy. Solvothermal treatment of hemin enabled the synthesized P-CHNPs to enhance oxidative stress in TME, which could be further amplified under light irradiation. Excellent in vitro and in vivo PDT effects were achieved due to the improved ROS (hydroxyl radicals and singlet oxygen) generation efficiency, hypoxia relief, and glutathione depletion. Moreover, the superior in vitro and in vivo biocompatibility and boosted PDT effect make the P-CHNPs a potential therapeutic agent for future translational research.

Engineering Macrophage Exosome Disguised Biodegradable Nanoplatform for Enhanced Sonodynamic Therapy of Glioblastoma.

Sonodynamic therapy (SDT) exhibits high tissue penetration and negligible radiation damage to normal tissues, and thus emerges as a promising cancer therapeutic modality for glioblastoma (GBM). However, the blood-brain barrier (BBB) and hypoxic microenvironment greatly limit the SDT efficiency. In this work, a biodegradable nanoplatform (termed as CSI) is fabricated by encapsulating catalase (CAT) into silica nanoparticles (CAT@SiO2 ) for tumor hypoxia relief, and then loaded with the sonosensitizer indocyanine green (ICG). Inspired by the ability of macrophages to cross the BBB, CSI is further coated with AS1411 aptamer-modified macrophage exosomes to form CSI@Ex-A, which possesses efficient BBB penetration and good cancer-cell-targeting capability. After tumor cell endocytosis, highly expressed glutathione (GSH) triggeres biodegradation of the nanoplatform and the released CAT catalyzes hydrogen peroxide (H2 O2 ) to produce O2 to relieve tumor hypoxia. The GSH depletion and O2 self-supplying effectively enhances the SDT efficiency both in vitro and in vivo. In addition, the resulting CSI@Ex-A exhibits good biocompatibility and long circulation time. These findings demonstrate that CSI@Ex-A may serve as a competent nanoplatform for GBM therapy, with potential for clinical translation.

Hybrid-Membrane-Decorated Prussian Blue for Effective Cancer Immunotherapy via Tumor-Associated Macrophages Polarization and Hypoxia Relief.

Both tumor-associated macrophages (TAMs) and hypoxia condition severely restrict the antitumor potency during cancer immunotherapy. It is essential to overcome the two issues for improving therapeutic efficacy. In this study, a hollow mesoporous Prussian blue (HMPB) nanosystem with mannose decoration and hydroxychloroquine (HCQ) adsorption is built, to form Man-HMPB/HCQ. It can facilitate cellular internalization via mannose-receptor mediated endocytosis and induce TAM polarization via iron ion/HCQ release with HMPB degradation. The hybrid macrophage and thylakoid (TK) membrane is camouflaged on the Man-HMPB/HCQ surface, denoted as TK-M@Man-HMPB/HCQ, to reduce in vivo reticuloendothelial system uptake, enhance tumor accumulation, and mitigate hypoxia. The in vivo results indicate that TK-M@Man-HMPB/HCQ notably inhibits tumor growth, induces TAM polarization, facilitates cytotoxic T lymphocytes infiltration, and alleviates hypoxia microenvironment. The rational design may provide a new pathway to modulate the tumor microenvironment for promoting cancer immunotherapy effects.

Engineering Cu-CuFe2O4 nanoenzyme for hypoxia-relief and GSH-depletion enhanced chemodynamic/sonodynamic therapy

Specific hypoxia and overexpressed glutathione (GSH) in the tumor microenvironment (TME) are bottleneck for reactive oxygen species (ROS)-involved therapy performance. Herein, we report a novel Cu-CuFe2O4 nanoenzyme enables simultaneous hypoxia relief and GSH depletion for efficiently augmenting ROS-involved chemodynamic (CDT)/sonodynamic (SDT) therapy. The nanoenzyme exhibited both catalase-like and GSH peroxidase-like catalytic activities, which can persistently catalyze tumor-overexpressed hydrogen peroxide (H2O2) to generate oxygen (O2) to facilitate singlet oxygen (1O2) production under an external ultrasound, achieving hypoxia-relieved SDT. Meanwhile, the Cu-CuFe2O4 NPs reacted with GSH to deplete GSH and release Fenton-like Cu+ and Fe2+ ions to mediate abundant hydroxyl radical (OH) production for CDT. Highly efficient anticancer ability of the Cu-CuFe2O4 NPs was demonstrated from the efficient MCF-7 cells killing and multicellular tumor spheroids (MCTS) elimination. This work provides a useful strategy to design multi-mode TME-responsive nanosonosensitizer for enhancing therapeutic effect of cancer therapy via persistent and simultaneous regulatory of TME, showing a great potential for clinical cancer therapy.

Nitric oxide nano-prodrug platform with synchronous glutathione depletion and hypoxia relief for enhanced photodynamic cancer therapy

Photodynamic therapy (PDT) is a promising non-invasive and selective cancer treatment. However, its efficacy is curtailed by tumor hypoxia and high levels of glutathione (GSH) in the tumor and addressing both limitations simultaneously remain challenging. Here, an all-in-one nanoplatform was designed using a GSH-responsive nitric oxide (NO) nano-prodrug that synchronously depletes GSH and relieves hypoxia in tumors, enhancing PDT efficacy. The nano-prodrug PEG-PAMAM-PA/SNO was prepared by integrating the GSH-sensitive NO and pheophorbide A (PA) prodrugs N-acetyl-d-penicillamine thiolactone and PAMAM-PA into polyethylene glycol (PEG), and the NPPA/NO and NPPA were then obtained through nanoprecipitation method. This nanoplatform depletes the intracellular antioxidant, GSH, by integrating GSH-responsive NO prodrug and generating NO that relaxes blood vessels, thereby relieving tumor hypoxia and defeating antioxidant defense system in tumor, while PEGylated PAMAM dendrimers have abundant surface functional groups and can greatly prolong their circulation lifetime in the bloodstream. These effects make this GSH-activatable NO nano-prodrug platform an appealing strategy for enhancing PDT's antitumor effects.

A pH-sensitive nanomedicine incorporating catalase gene and photosensitizer augments photodynamic therapy and activates antitumor immunity

Immunological "cold" tumors including most triple-negative breast cancers (TNBCs) hardly respond to immunotherapy due to their extreme immunosuppressive microenvironment. Among various immunosuppressive factors, hypoxia provides a vital target for boosting antitumor immunotherapy as it plays a key role in mediating adaptive immune resistance of tumors. Here, a multifunctional nanomedicine incorporating a plasmid DNA encoding catalase gene (pDNA-cat) and photosensitizer Ce6 was developed to elicit robust immunity via photodynamic therapy (PDT) and hypoxia alleviation. The pH-sensitive sheddable coating of nanomedicine facilitated the codelivery of Ce6 and pDNA-cat into tumor cells. Under near-infrared laser irradiation, Ce6 generated cytotoxic reactive oxygen species (ROS) to induce immunogenic cell death (ICD), which promoted the maturation of dendric cells (DCs) and tumor infiltration of antitumor T cells. Meanwhile, tumor cells transfected with pDNA-cat expressed catalase to catalyze the O2 production from tumor-enriched H2O2in situ. Tumor hypoxia relief not only augmented photodynamic therapy (PDT) known as an oxygen-consuming process but also induced strong antitumor immunity. Consequently, the multifunctional nanomedicine demonstrated strong efficacy to inhibit the tumor growth and recurrence.

All-in-one Cu-mediated Ag-assembled nanocomposites for photothermal-assisted photo/chemical dynamic therapy with hypoxia relief and enhanced reactive oxygen species

A multimodal anti-tumor nano-agent enhanced the efficiency of photodynamic therapy via photothermal therapy, alleviating hypoxia and Cu2+-mediated reactions.

Surface Engineered Iron Oxide Nanozyme for Synergistic Chemodynamic/Photodynamic Therapy with Glutathione Depletion and Hypoxia Relief

Surface Engineered Iron Oxide Nanozyme for Synergistic Chemodynamic/Photodynamic Therapy with Glutathione Depletion and Hypoxia Relief

Graphene-containing metal-organic framework nanocomposites for enhanced microwave ablation of salivary adenoid cystic carcinoma.

Salivary adenoid cystic carcinoma (SACC), one of the most common malignant tumors in the head and neck region, is characterized by high postoperative recurrence rate and poor prognosis. Microwave (MW) ablation possesses advantages in preserving SACC patients' facial aesthetics and oral function, but unfortunately, it suffers from low therapeutic efficacy due to the limited MW-thermal efficiency. Moreover, the insufficient thermal ablation may aggravate hypoxic state in tumors, which is deleterious to the treatment of residual tumors and aggressive tumors. Hence, MW ablation has been rarely applied in treating head and neck tumors in recent years. To minimize the unfavorable outcomes and maximize the therapeutic effects of MW ablation, a MW sensitizer coupled with a self-sufficient oxygen nanoagent was employed for the first time in MW ablation to treat head and neck tumors. We prepared a graphene-containing metal–organic framework (ZIF67@Gr-PEG), which exhibited excellent MW thermal conversion ability endowed by the incorporated Gr and showed in situ oxygen generation capacity derived from the ZIF67 matrix. In an animal experiment, ZIF67@Gr-PEG-based MW ablation with a temperature up to 66.1 °C exhibited a high tumor ablation rate. More importantly, insufficient MW ablation-induced high expressions of HIF-1α and VEGF were observed in our experiment, whereas the levels of tumor hypoxia and angiogenesis were efficiently decreased in MW ablation with the assistance of ZIF67@Gr-PEG nanocomposites (NCs). Notably, our strategy for MW ablation not only evidences the great potential of ZIF67@Gr-PEG but also promotes the translation of thermotherapeutic graphene from basic research to clinical practice.

A multifunctional nanoamplifier with self-enhanced acidity and hypoxia relief for combined photothermal/photodynamic/starvation therapy

Phototherapies, including photothermal therapy (PTT) and photodynamic therapy (PDT) have been potential noninvasive therapeutic modality with high efficiency, however, there still exist some intrinsic limitations that impede their clinical applications. Herein, taking the advantages of the synergistic effect and high reactivity of manganese dioxide (MnO2) nanosheets and glucose oxidase (GOx), multifunctional MPDA@MnO2-MB-GOx nanoamplifier was constructed for enhanced PTT, PDT, and starvation therapy. In tumor microenvironment (TME), MnO2 nanosheets on the surface of mesoporous polydopamine (MPDA) could react with endogenous hydrogen peroxide (H2O2) and generate oxygen (O2) to relieve tumor hypoxia, thus enhancing the efficacy of PDT and GOx catalysis. Glucose consumption under the catalysis of GOx will enhance the acidity of TME and increase intracellular H2O2 concentration, which in turn promotes the production of O2 by MnO2 nanosheets, thus forming efficient cascade reaction and maximizing the efficacy of the functional agents. Furthermore, the heat generated by MPDA under the irradiation of 808 nm laser can accelerate chemical reactions, thus further enhancing synergistic therapeutic efficacy. In vitro/vivo results emphasize that enhanced cancer cell death and tumor inhibition are gained by modulating unfavorable TME with the functional nanosystem, which highlights the promise of the synthesized MPDA@MnO2-MB-GOx nanomaterial to overcome the limitations of phototherapy.

Perfluorocarbon loaded fluorinated covalent organic polymers with effective sonosensitization and tumor hypoxia relief enable synergistic sonodynamic-immunotherapy

Relieving tumor hypoxia has recently been found to be a promising approach to reverse tumor immunosuppression and thus enhance the treatment outcomes of diverse cancer treatments. Herein, we prepared a type of fluorinated covalent conjugate polymers (COPs) with sonosensitizer meso-5, 10, 15, 20-tetra (4-hydroxylphenyl) porphyrin (THPP) and perfluorosebacic acid (PFSEA) as cross-linkers, yielding THPPpf-COPs with efficient sonodynamic efficacy and loading capacity towards perfluoro-15-crown-5-ether (PFCE), a model perfluorocarbon molecule. Upon intratumoral injection, such PFCE@THPPpf-COPs could not only attenuate tumor hypoxia, but also exhibit the most effective suppression effect on tumor growth in the presence of ultrasound exposure by inducing immunogenic cell death of cancer cells. Furthermore, we found that the sonodynamic therapy of PFCE@THPPpf-COPs together with anti-CD47 immunotherapy would synergistically suppress tumor growth by increasing the tumor-infiltrating frequencies of phagocytic M1 macrophages and cytotoxic CD3+CD8+ T cells, while reducing the frequency of immunosuppressive regulatory T cells. Moreover, such combination treatment could also elicit potent protective memory antitumor immunity to prevent tumor challenge. Therefore, this work presents PFCE@THPPpf-COPs are a type of multifunctional nano-sonosensitizers potent in removing negative impacts of inherent tumor hypoxia and immunosuppression, and suppressing tumor growth and tumor recurrence by priming host's antitumor immunity, particularly in synergizing with anti-CD47 immunotherapy.

Smart Tumor-Cell-Derived Microparticles Provide On-Demand Photosensitizer Synthesis and Hypoxia Relief for Photodynamic Therapy.

Positioning essential elements of photodynamic therapy (PDT) near to mitochondria can conquer the rigorous spatiotemporal limitations of reactive oxygen species (ROS) transfer and make considerable differences in PDT. However, precise accumulation of photosensitizer (PS) and oxygen within mitochondria is still challenging. We simultaneously encapsulated hexyl 5-aminolevulinate hydrochloride (HAL) and 3-bromopyruvic acid (3BP) into microparticles collected from X-ray-irradiated tumor cells (X-MP). After systemic administration, the developed HAL/3BP@X-MP can specifically target and recognize tumor cells, where HAL induces efficient accumulation of PpIX in mitochondria via the intrinsic haem biosynthetic pathway. Meanwhile, 3BP remarkably increases the oxygen supply by inhibiting mitochondrial respiration. The accurate co-localization and prompt encounter of PpIX and oxygen produce sufficient ROS to directly disrupt mitochondria, resulting in significantly improved PDT outcomes.

Smart Tumor‐Cell‐Derived Microparticles Provide On‐Demand Photosensitizer Synthesis and Hypoxia Relief for Photodynamic Therapy

AbstractPositioning essential elements of photodynamic therapy (PDT) near to mitochondria can conquer the rigorous spatiotemporal limitations of reactive oxygen species (ROS) transfer and make considerable differences in PDT. However, precise accumulation of photosensitizer (PS) and oxygen within mitochondria is still challenging. We simultaneously encapsulated hexyl 5‐aminolevulinate hydrochloride (HAL) and 3‐bromopyruvic acid (3BP) into microparticles collected from X‐ray‐irradiated tumor cells (X‐MP). After systemic administration, the developed HAL/3BP@X‐MP can specifically target and recognize tumor cells, where HAL induces efficient accumulation of PpIX in mitochondria via the intrinsic haem biosynthetic pathway. Meanwhile, 3BP remarkably increases the oxygen supply by inhibiting mitochondrial respiration. The accurate co‐localization and prompt encounter of PpIX and oxygen produce sufficient ROS to directly disrupt mitochondria, resulting in significantly improved PDT outcomes.

Glucose/Glutathione Co-triggered Tumor Hypoxia Relief and Chemodynamic Therapy to Enhance Photothermal Therapy in Bladder Cancer.

Photothermal therapy (PTT) is a potential treatment for cancer that makes use of near-infrared (NIR) laser irradiation and is expected to assist traditional anti-cancer drug therapies; however, the therapeutic efficacy of PTT is restricted by thermal resistance due to the overexpression of heat shock proteins and insufficient penetration depth of lasers. Thus, PTT needs to be combined with additional therapeutic methods to obtain the optimal therapeutic efficacy for cancer. Herein, a multifunctional therapeutic platform combining PTT with glucose-triggered chemodynamic therapy (CDT) and glutathione (GSH)-triggered hypoxia relief was developed via GOx@MBSA-PPy-MnO2 NPs (GOx for glucose oxidase, M for Fe3O4, BSA for bovine serum albumin, and PPy for polypyrrole). GOx@MBSA-PPy-MnO2 NPs have excellent photothermal efficiency and can release Mn2+, which catalyzes the transformation of H2O2 into hydroxyl radicals (·OH) and O2 via a Fenton-like reaction, effectively destroying cancer cells and relieving tumor hypoxia. Meanwhile, a high content of H2O2 was produced via GOx catalysis of glucose, further enhancing the CDT efficiency. In addition, in vitro and in vivo experiments showed that the inhibition of cancer cell proliferation and effective inhibition of tumors could be caused by the combined PTT/glucose-triggered CDT effects and hypoxia relief of the GOx@MBSA-PPy-MnO2 NPs. Overall, this work provides evidence of a synergistic therapy that remarkably improves therapeutic efficacy and significantly prolongs the lifetime of mice compared with controls.

Regulation of zeolite-derived upconversion photocatalytic system for near infrared light/ultrasound dual-triggered multimodal melanoma therapy under a boosted hypoxia relief tumor microenvironment via autophagy

Reactive oxygen species (ROS) production efficiency, tumor microenvironment hypoxia relief, and autophagy-induced cell death with minimal negative effects are considered the main objectives to achieve more efficient tumor treatment. However, realizing highly effective cancer treatment under hypoxia relief with a cell autophagy model based on suitable biomaterials is still a challenge. Herein, a biosafe upconversion nanomaterial based on Linde Type A (LTA) zeolites loaded with carbon nitride (C3N4) photocatalyst and chlorin e6 (Ce6) was developed as a rationally regulated photocatalytic system and multimodal tumor therapeutic platform. C3N4 contributes to stability, tumor hypoxia relief, high surface conductivity and high drug-loading. Remarkably, photodynamic therapy (PDT) and sonodynamic therapy (SDT) were proven capable of maximizing the ROS yield to obtain highly tumor therapeutic outcomes. Photothermal conversion efficiency was 46.72%. Furthermore, internalized nanomaterials can result in tumor inhibition through cell autophagy. The as-developed system shows a promising potential in the multimodal cancer therapeutics.

E. coli Membrane Vesicles as a Catalase Carrier for Long-Term Tumor Hypoxia Relief to Enhance Radiotherapy.

Hypoxia is one of the most important factors that limit the effect of radiotherapy, and the abundant H2O2 in tumor tissues will also aggravate hypoxia-induced radiotherapy resistance. Delivering catalase to decompose H2O2 into oxygen is an effective strategy to relieve tumor hypoxia and radiotherapy resistance. However, low stability limits catalase's in vivo application, which is one of the most common limitations for almost all proteins' internal utilization. Here, we develop catalase containing E. coli membrane vesicles (EMs) with excellent protease resistance to relieve tumor hypoxia for a long time. Even treated with 100-fold of protease, EMs showed higher catalase activity than free catalase. After being injected into tumors post 12 h, EMs maintained their hypoxia relief ability while free catalase lost its activity. Our results indicate that EMs might be an excellent catalase delivery for tumor hypoxia relief. Combined with their immune stimulation features, EMs could enhance radiotherapy and induce antitumor immune memory effectively.