Acidity-Responsive Nanoreactors Destructed "Warburg Effect" for Toxic-Acidosis and Starvation Synergistic Therapy.

"Warburg Effect" shows that most tumor cells rely on aerobic glycolysis for energy supply, leading to malignant energy deprivation and an "internal alkaline external acid" tumor microenvironment. Destructing the "Warburg Effect" is an effective approach to inhibit tumor progression. Herein, an acidity-responsive nanoreactor (Au@CaP-Flu@HA) is fabricated for toxic acidosis and starvation synergistic therapy. In the nanoreactor, the fluvastatin (Flu) could reduce lactate efflux by inhibiting the lactate-proton transporter (monocarboxylate transporters, MCT4), resulting in intracellular lactate accumulation. Meanwhile, the glucose oxidase-mimic Au-nanocomposite consumes glucose to induce cell starvation accompanied by gluconic acid production, coupling with lactate to exacerbate toxic acidosis. Also, the up-regulated autophagic energy supply of tumor cells under energy deprivation and hypoxia aggravation is blocked by autophagy inhibitor CaP. Cellular dysfunction under pHi acidification and impaired Adenosine Triphosphate (ATP) synthesis under starvation synergistically promote tumor cell apoptosis. Both in vitro and in vivo studies demonstrate that this combinational approach of toxic-acidosis/starvation therapy could effectively destruct the "Warburg Effect" to inhibit tumor growth and anti-metastatic effects.

PtMo-Au Metalloenzymes Regulated Tumor Microenvironment for Enhanced Sonodynamic/Chemodynamic/Starvation Synergistic Therapy.

The clinical application of sonodynamic therapy (SDT) is greatly limited by the low quantum yield of sonosensitizers and tumor microenvironment (TME). Herein, PtMo-Au metalloenzyme sonosensitizer is synthesized by modulating energy band structure of PtMo with Au nanoparticles. The surface deposition of Au simultaneously solves the carrier recombination and facilitates the separation of electrons (e- ) and holes (h+ ), effectively improving the reactive oxygen species (ROS) quantum yield under ultrasound (US). The catalase-like activity of PtMo-Au metalloenzymes alleviates hypoxia TME, thus enhancing the SDT-induced ROS generation. More importantly, tumor overexpressed glutathione (GSH) can serve as the hole scavenger, which is accompanied by a persistent depletion of the GSH, thus inactivating GPX4 for the accumulation of lipid peroxides. The distinctly facilitated SDT-induced ROS production is coupled with chemodynamic therapy (CDT)-induced hydroxyl radicals (•OH) to exacerbate ferroptosis. Furthermore, Au with glucose oxidase mimic activity can not only inhibit intracellular adenosine triphosphate (ATP) production and induce tumor cell starvation but also generate H2 O2 to facilitate CDT. In general, this PtMo-Au metalloenzyme sonosensitizer optimizes the defects of conventional sonosensitizers through surface deposition of Au to regulate TME, providing a novel perspective for US-based tumor multimodal therapy.

CD133-Targeted Hybrid Nanovesicles for Fluorescent/Ultrasonic Imaging-Guided HIFU Pancreatic Cancer Therapy.

Background: Pancreatic cancer is regarded as one of the most lethal types of tumor in the world, and optional way to treat the tumor are urgently needed. Cancer stem cells (CSCs) play a key role in the occurrence and development of pancreatic tumors. CD133 is a specific antigen for targeting the pancreatic CSCs subpopulation. Previous studies have shown that CSC-targeted therapy is effective in inhibiting tumorigenesis and transmission. However, CD133 targeted therapy combined with HIFU for pancreatic cancer is absent. Purpose: To improve therapeutic efficiency and minimize side effects, we carry a potent combination of CSCs antibody with synergist by an effective and visualized delivery nanocarrier to pancreatic cancer. Materials and Methods: Multifunctional CD133-targeted nanovesicles (CD133-grafted Cy5.5/PFOB@P-HVs) with encapsulated perfluorooctyl bromide (PFOB) in a 3-mercaptopropyltrimethoxysilane (MPTMS) shell modified with poly ethylene glycol (PEG) and superficially modified with CD133 and Cy 5.5 were constructed following the prescribed order. The nanovesicles were characterized for the biological and chemical characteristics feature. We explored the specific targeting capacity in vitro and the therapeutic effect in vivo. Results: The in vitro targeting experiment and in vivo FL and ultrasonic experiments showed the aggregation of CD133-grafted Cy5.5/PFOB@P-HVs around CSCs. In vivo FL imaging experiments demonstrated that the nanovesicles assemble for the highest concentration in the tumor at 24 h after administration. Under HIFU irradiation, the synergistic efficacy of the combination of the CD133-targeting carrier and HIFU for tumor treatment was obvious. Conclusion: CD133-grafted Cy5.5/PFOB@P-HVs combined with HIFU irradiation could enhance the tumor treatment effect not only by improving the delivery of nanovesicles but also by enhancing the HIFU thermal and mechanical effects in the tumor microenvironment, which is a highly effective targeted therapy for treating pancreatic cancer.

A novel VEGFR inhibitor ZLF-095 with potent antitumor activity and low toxicity.

Angiogenesis plays a critical role in the survival, progression and metastasis of malignant tumors. Multiple factors are known to induce tumor angiogenesis, vascular endothelial growth factor (VEGF) is the most important one. Lenvatinib is an oral multi-kinase inhibitor of VEGFRs which has been approved for the treatment of various malignancies as the first-line agent by the Food and Drug Administration (FDA). It shows excellent antitumor efficacy in clinical practice. However, the adverse effects of Lenvatinib may seriously impair the therapeutic effect. Here we report the discovery and characterization of a novel VEGFR inhibitor (ZLF-095), which exhibited high activity and selectivity for VEGFR1/2/3. ZLF-095 displayed apparently antitumor effect in vitro and in vivo. We discovered that Lenvatinib could provoke fulminant ROS-caspase3-GSDME-dependent pyroptosis in GSDME-expressing cells by loss of mitochondrial membrane potential, which may be one of the reasons for Lenvatinib's toxicity. Meanwhile, ZLF-095 showed less toxicity than Lenvatinib by switching pyroptosis to apoptosis. These results suggest that ZLF-095 could become a potential angiogenesis inhibitor for cancer therapy.

Multifaceted Roles of Copper Ions in Anticancer Nanomedicine.

The significantly increased copper level in tumor tissues and serum indicates the close association of copper ions with tumor development, making copper ions attractive targets in the development of novel tumor treatment methods. The advanced nanotechnology developed in the past decades provides great potential for tumor therapy, among which Cu-based nanotherapeutic systems have received greater attention. Herein, the multifaceted roles of copper ions in cancer progression are summarized and the recent advances in the copper-based nanostructures or nanomedicines for different kinds of tumor therapies including copper depletion therapy, copper-based cytotoxins, copper-ion-based chemodynamic therapy and its combination with other treatments, and copper-ion-induced ferroptosis and cuproptosis activation are discussed. Furthermore, the perspectives for the further development of copper-ion-based nanomedicines for tumor therapy and clinic translation are presented by the authors.

Acidity-responsive nanoplatforms aggravate tumor hypoxia via multiple pathways for amplified chemotherapy.

Since the hypoxia tumor microenvironment (TME) will not only limit the treatment effect but also cause tumor recurrence and metastasis, intratumoral aggravated hypoxia level induced by vascular embolization is one of the major challenges in tumor therapy. The chemotherapeutic effect of hypoxia-activated prodrugs (HAPs) could be enhanced by the intensified hypoxia, the combination of tumor embolization and HAP-based chemotherapy exhibits a promising strategy for cancer therapy. Herein, an acidity-responsive nanoplatform (TACC NP) with multiple pathways to benefit the hypoxia-activated chemotherapy is constructed by loading the photosensitizer Chlorin e6 (Ce6), thrombin (Thr), and AQ4N within the calcium phosphate nanocarrier via a simple one-pot method. In the acidic TME, TACC NPs could be degraded to release Thr and Ce6, resulting in the destruction of tumor vessels and consumption of intratumoral oxygen under laser irradiation. Therefore, the intratumoral hypoxia level could be significantly aggravated, further leading to the enhanced chemotherapeutic effect of AQ4N. With the guidance of in vivo fluorescence imaging, the TACC NPs exhibited excellent tumor embolization/photodynamic/prodrug synergistic therapeutic effects with good biosafety.

Pharmacological inhibition of EZH2 by ZLD1039 suppresses tumor growth and pulmonary metastasis in melanoma cells in vitro and in vivo.

The incidence and mortality rate of malignant melanoma are increasing worldwide. Metastasis reduces the efficacy of current melanoma therapies and leads to poor prognosis for patients. EZH2 is a methyltransferase that promotes the proliferation, metastasis, and drug resistance of tumor cells by regulating transcriptional activity. EZH2 inhibitors could be effective in melanoma therapies. Herein, we aimed to investigate whether the pharmacological inhibition of EZH2 by ZLD1039, a potent and selective S-adenosyl-l-methionine-EZH2 inhibitor, suppresses tumor growth and pulmonary metastasis in melanoma cells. Results showed that ZLD1039 selectively reduced H3K27 methylation in melanoma cells by inhibiting EZH2 methyltransferase activity. Additionally, ZLD1039 exerted excellent antiproliferative effects on melanoma cells in 2D and 3D culture systems. Administration of ZLD1039 (100 mg/kg) by oral gavage caused antitumor effects in the A375 subcutaneous xenograft mouse model. RNA sequencing and GSEA revealed that the ZLD1039-treated tumors exhibited changes in the gene sets enriched from the "Cell Cycle" and "Oxidative Phosphorylation", whereas the "ECM receptor interaction" gene set had a negative enrichment score. Mechanistically, ZLD1039 induced G0/G1 phase arrest by upregulating p16 and p27 and inhibiting the functions of the cyclin D1/CDK6 and cyclin E/CDK2 complexes. Moreover, ZLD1039 induced apoptosis in melanoma cells via the mitochondrial reactive oxygen species apoptotic pathway, consistent with the changes in transcriptional signatures. ZLD1039 also exhibited excellent antimetastatic effects on melanoma cells in vitro and in vivo. Our data highlight that ZLD1039 may be effective against melanoma growth and pulmonary metastasis and thus could serve as a therapeutic agent for melanoma.

Potent nanoreactor-mediated ferroptosis-based strategy for the reversal of cancer chemoresistance to Sorafenib.

The drug resistance of cancer cells is related to a variety of mechanisms, among which the destruction of redox homeostasis is one of the key factors. Ferroptosis, an intracellular iron-dependent form of cell death, is related to the production of oxidative stress. The accumulation of lipid peroxidation (LPO) during ferroptosis disrupts intracellular redox homeostasis, thereby affecting the sensitivity of tumor cells to drugs. In this work, we proposed a ferroptosis strategy based on LPO accumulation, reduced glutathione generation via inhibition of SLC3A2 protein and inactivated glutathione peroxidase 4 (GPX4) to reverse the chemoresistance of cancer cells. The Fenton reaction based on the ferroptosis-inducing nanoreactors (Au/Fe-GA/Sorafenib@PEG) not only generated hydroxyl radicals (·OH) under laser irradiation to realize the accumulation of LPO, but also depleted GSH to increase the accumulation of LPO. Meanwhile, the cystine uptake of cells was inhibited by Sorafenib, resulting in reduced GSH synthesis and inactivated GPX4. In vitro and in vivo experiments demonstrated AFG/SFB@PEG + Laser group could inactivate GPX4 and the enhanced ferroptosis can reverse chemo-resistance caused by continuous upregulation of GPX4 levels in cells through 'self-rescue'. The study proposed the mechanism and feasibility of ferroptosis to reverse drug resistance, providing a promising strategy for chemo-resistant cancer treatment. STATEMENT OF SIGNIFICANCE: Herein, we proposed a ferroptosis strategy based on LPO accumulation, reduced glutathione generation via inhibition of SLC3A2 protein, and inactivated glutathione peroxidase 4 (GPX4) to reverse chemoresistance of cancer cells. The Fenton reaction based on the ferroptosis-inducing nanoreactors (Au/Fe-GA/Sorafenib@PEG) not only generated hydroxyl radicals (·OH) under laser irradiation to realize the accumulation of LPO but also depleted GSH to increase the accumulation of LPO. Meanwhile, the cystine uptake of cells was inhibited by Sorafenib, resulting in reduced GSH synthesis and inactivated GPX4. In vitro and in vivo experiments demonstrated AFG/SFB@PEG + Laser group could inactivate GPX4 and the enhanced ferroptosis can reverse chemo-resistance caused by continuous upregulation of GPX4 levels in cells through 'self-rescue'.

Endogenous/Exogenous Nanovaccines Synergistically Enhance Dendritic Cell-Mediated Tumor Immunotherapy.

Traditional dendritic cell (DC)-mediated immunotherapy is usually suppressed by weak immunogenicity in tumors and generally leads to unsatisfactory outcomes. Synergistic exogenous/endogenous immunogenic activation can provide an alternative strategy for evoking a robust immune response by promoting DC activation. Herein, Ti3 C2 MXene-based nanoplatforms (termed MXP) are prepared with high-efficiency near-infrared photothermal conversion and immunocompetent loading capacity to form endogenous/exogenous nanovaccines. Specifically, the immunogenic cell death of tumor cells induced by the photothermal effects of the MXP can generate endogenous danger signals and antigens release to boost vaccination for DC maturation and antigen cross-presentation. In addition, MXP can deliver model antigen ovalbumin (OVA) and agonists (CpG-ODN) as an exogenous nanovaccine (MXP@OC), which further enhances DC activation. Importantly, the synergistic strategy of photothermal therapy and DC-mediated immunotherapy by MXP significantly eradicates tumors and enhances adaptive immunity. Hence, the present work provides a two-pronged strategy for improving immunogenicity and killing tumor cells to achieve a favorable outcome in tumor patients.

Injectable Tissue-Adhesive Hydrogel for Photothermal/Chemodynamic Synergistic Antibacterial and Wound Healing Promotion.

It is an exigent need for the development of hydrogel dressings with desirable injectability, good adhesive, antibacterial, and wound healing promotion properties. Herein, the multifunctional injectable hydrogels with good tissue adhesion are designed based on Ag-doped Mo2C-derived polyoxometalate (AgPOM) nanoparticles, urea, gelatin, and tea polyphenols (TPs) for antibacterial and wound healing acceleration. After being injected into the tissue, urea diffuses out under the concentration gradient, and TPs and gelatin chains recombine to trigger the in situ formation of hydrogel with excellent adhesiveness. AgPOM fixed in the hydrogel could not only react with hydrogen peroxide in the infection site to generate singlet oxygen to kill the bacteria but also convert near-infrared light into heat under 1060 nm laser irradiation to realize sterilization. In vitro studies display the high bactericidal ability of the hydrogel against drug-resistant Staphylococcus aureus and also exhibit a prominent therapeutic effect on infected wounds through synergistic photothermal/chemodynamic therapy and accelerate wound healing. Hence, the injectable hydrogel with AgPOM as the antimicrobial agent can be a novel therapeutic agent for drug-resistant bacteria-infected wounds and wound healing promotion.

Brain Proteome-Wide and Transcriptome-Wide Asso-ciation Studies, Bayesian Colocalization, and Mendelian Randomization Analyses Reveal Causal Genes of Parkinson's Disease.

How genome-wide associated loci confer risk for Parkinson's disease is unclear. We aim to reveal causal genes through effects on brain proteins to provide new pathogenesis insights for Parkinson's disease. Proteome-wide and transcriptome-wide associations were determined by functional summary-based imputation leveraging data from genome-wide association summary (56 306 Europeans, 1.4 million controls), brain proteomes (528 cases from 2 separate data sets), and transcriptome (452 cases), followed by Mendelian randomization, Bayesian colocalization, cell-type-specific and brain regional expression, and drug-gene interaction analyses. As a result, genetically regulated protein abundances of 11 genes were associated with Parkinson's disease. Five genes (CD38, GPNMB, TMEM175, RAB7L1, and HIP1R) were colocalized. Four genes (GPNMB, SEC23IP, CD38, and DGKQ) demonstrated Mendelian randomized correlations (p < 8.10 × 10-5). Higher GPNMB level (1.47, 1.28-1.68) and lower CD38 level (0.319, 0.24-0.43) were causally associated with higher risk of Parkinson's disease, consistent with transcriptomic evaluations. CD38 and GPNMB were preferentially enriched in astrocytes and oligodendrocyte precursor cells, respectively. And CD38 and GPNMB were suggested to be the targets of many oncological drugs from Drug-Gene Interaction database. In conclusion, utilizing multidimensional data, GPNMB and CD38 were prioritized as the causal genes of Parkinson's disease, crucial for mechanistic and therapeutic investigations.

Multifunctional nanolocks with GSH as the key for synergistic ferroptosis and anti-chemotherapeutic resistance.

The emergence of chemotherapeutic resistance, which is closely related to the oxidative stress defense induced by the imbalance of reactive oxygen species (ROS), is one of the important reasons for the failure of anti-tumor therapy. Herein, a GSH-triggered ferroptosis/apoptosis integrated tumor therapy strategy was successfully implemented to prohibit the mitoxantrone (MTO) resistance. Owing to the overexpressed GSH in the tumor microenvironment, the tumor active targeting MTO-Cu(Ⅱ)-cRGD nanolocks could be dissociated to release Cu(Ⅰ) and MTO, which could persistently catalyze hydrogen peroxide into hydroxyl radicals (•OH) via Fenton-like reaction and generate photothermal effect, respectively. The depletion of GSH inactivated GPX4 for the accumulation of lipid peroxides (LPO) and inducing ferroptosis. With the destruction of oxidative stress defenses, the formation of chemotherapeutic resistance could be effectively prohibited. The nanolocks could eliminate the solid tumors through ferroptosis-sensitized chemotherapy under the guidance of photoacoustic imaging. The study proposed the mechanism of reversing chemotherapeutic resistance by ferroptosis, providing a feasible strategy for the treatment of drug-resistant tumors.

Zn(ii)-Coordination-driven self-assembled nanoagents for multimodal imaging-guided photothermal/gene synergistic therapy.

Synergistic photothermal therapy (PTT) with gene therapy (GT) has drawn emerging interest in the improvement of cancer therapeutic efficiency, while the co-delivery of photothermal agents (PTAs) and therapeutic genes by an integrated nanoplatform, with controllability and biodegradability, is still challenging and urgently desired. Herein, a multi-functional metal-organic framework (MOF) based PTT-GT platform (siRNA@PT-ZIF-8) was developed, which was constructed with siRNA, a near-infrared (NIR) responsive organic dye IR780 derivative (IR780-1), and 2-methylimidazole (2-MIM) by a facile one-pot self-assembly method. This "all-in-one" system of siRNA@PT-ZIF-8 enabled not only photothermal/photoacoustic/fluorescence multimodal imaging but also tumor microenvironment responsiveness for specific and on-demand release of therapeutic cargos, overcoming the inherent limitations of free gene or organic PTA molecules (e.g., short blood circulation half-life and weak stability) in conventional PTT and GT. This nanoplatform provides an efficient and safe strategy for cancer theranostics, and the one-step assembly strategy favors personalized formulation design for diverse demands in cancer management.

Recent advances in smart nanoplatforms for tumor non-interventional embolization therapy.

Tumor embolization therapy has attracted great attention due to its high efficiency in inhibiting tumor growth by cutting off tumor nutrition and oxygen supply by the embolic agent. Although transcatheter arterial embolization (TAE) is the mainstream technique in the clinic, there are still some limitations to be considered, especially the existence of high risks and complications. Recently, nanomaterials have drawn wide attention in disease diagnosis, drug delivery, and new types of therapies, such as photothermal therapy and photodynamic therapy, owing to their unique optical, thermal, convertible and in vivo transport properties. Furthermore, the utilization of nanoplatforms in tumor non-interventional embolization therapy has attracted the attention of researchers. Herein, the recent advances in this area are summarized in this review, which revealed three different types of nanoparticle strategies: (1) nanoparticles with active targeting effects or stimuli responsiveness (ultrasound and photothermal) for the safe delivery and responsive release of thrombin; (2) tumor microenvironment (copper and phosphate, acidity and GSH/H2O2)-responsive nanoparticles for embolization therapy with high specificity; and (3) peptide-based nanoparticles with mimic functions and excellent biocompatibility for tumor embolization therapy. The benefits and limitations of each kind of nanoparticle in tumor non-interventional embolization therapy will be highlighted. Investigations of nanoplatforms are undoubtedly of great significance, and some advanced nanoplatform systems have arrived at a new height and show potential applications in practical applications.

Starvation, Ferroptosis, and Prodrug Therapy Synergistically Enabled by a Cytochrome c Oxidase like Nanozyme.

Nanozymes, which are inorganic nanomaterials mimicking natural enzyme activities, are bringing enormous opportunities to theranostics. Herein, a cytochrome c oxidase-like nanozyme (copper-silver alloy nanoparticle, Cu-Ag NP) is demonstrated for nanocatalytic cancer therapy. Loaded with bioreductive predrug (AQ4N), this Cu-Ag nanozyme unprecedentedly enables simultaneous starvation, ferroptosis, and chemical therapy with high specificity, and is able to totally eliminate tumor and greatly prolong the survival rate for 4T1-tumor-bearing mice. The underlying working mechanism is revealed both experimentally and theoretically.

Recent advances of cancer chemodynamic therapy based on Fenton/Fenton-like chemistry.

Applying Fenton chemistry in the tumor microenvironment (TME) for cancer therapy is the most significant feature of chemodynamic therapy (CDT). Owing to the mild acid and overexpressed H2O2 in TME, more cytotoxic hydroxyl radicals (˙OH) are generated in tumor cells via Fenton and Fenton-like reactions. Without external stimulus and drug resistance generation, reactive oxygen species (ROS)-mediated CDT exhibits a specific and desirable anticancer effect and has been seen as a promising strategy for cancer therapy. However, optimizing the treatment efficiency of CDT in TME is still challenging because of the limited catalytic efficiency of CDT agents and the strong cancer antioxidant capacity in TME. Hence, scientists are trying their best to design and fabricate many more CDT agents with excellent catalytic activity and remodeling TME for optimal CDT. In this perspective, the latest progress of CDT is discussed, with some representative examples presented. Consequently, promising strategies for further optimizing the efficiency of CDT guided by Fenton chemistry are provided. Most importantly, several feasible ways of developing CDT in the future are offered for reference.

Injectable hydrogel for postoperative synergistic photothermal-chemodynamic tumor and anti-infection therapy.

Tumor surgery is usually accompanied by neoplasm residual, tissue defects, and multi-drug resistant bacterial infection, causing high tumor recurrence, low survival rate, and chronic wounds. Herein, a light-activated injectable hydrogel based on bioactive nanocomposite system is developed by incorporating Ag2S nanodots conjugated Fe-doped bioactive glass nanoparticles (BGN-Fe-Ag2S) into biodegradable PEGDA and AIPH solution for inhibiting tumor growth, treating bacterial infection, and promoting wound healing. Under laser irradiation, the photothermal effect mediated by Ag2S nanodots would trigger the decomposition of AIPH, generating alkyl radicals to initiate the gelation of PEGDA. The in-situ gelatinized hydrogel, with outstanding photothermal effect and chemodynamic effect derived from the doped Fe in BGN-Fe-Ag2S, can not only eliminate multidrug-resistant bacteria but also efficiently ablated tumor during treatment. Moreover, the hydrogel significantly accelerated wound healing with more skin appendages in the full-thickness cutaneous wounds model because of the hydrolysis of bioactive glass. These results manifest that this multifunctional hydrogel is a suitable biomaterial to inhibit tumor proliferation and overcome tissue bacterial infection after surgical removal of tumors.