STING activation disrupts tumor vasculature to overcome the EPR limitation and increase drug deposition.

The low success rate of cancer nanomedicines has raised debate on the role of the enhanced permeability and retention (EPR) effect on tumor deposition of nanotherapeutics. Here, we report a bifunctional nanoscale coordination polymer (NCP), oxaliplatin (OX)/2',3'-cyclic guanosine monophosphate-adenosine monophosphate (GA), to overcome the EPR limitation through stimulator of interferon genes (STING) activation and enhance chemotherapeutic and STING agonist delivery for tumor eradication. OX/GA encapsulates GA and OX in the NCP to protect GA from enzymatic degradation and improve GA and OX pharmacokinetics. STING activation by OX/GA disrupts tumor vasculatures and increases intratumoral deposition of OX by 4.9-fold over monotherapy OX-NCP. OX/GA demonstrates exceptional antitumor effects with >95% tumor growth inhibition and high cure rates in subcutaneous, orthotopic, spontaneous, and metastatic tumor models. OX/GA induces immunogenic cell death of tumor cells and STING activation of innate immune cells to enhance antigen presentation. NCPs provide an excellent nanoplatform to overcome the EPR limitation for effective cancer therapy.

Simultaneous Protonation and Metalation of a Porphyrin Covalent Organic Framework Enhance Photodynamic Therapy.

Covalent organic frameworks (COFs) have been explored for photodynamic therapy (PDT) of cancer, but their antitumor efficacy is limited by excited state quenching and low reactive oxygen species generation efficiency. Herein, we report a simultaneous protonation and metalation strategy to significantly enhance the PDT efficacy of a nanoscale two-dimensional imine-linked porphyrin-COF. The neutral and unmetalated porphyrin-COF (Ptp) and the protonated and metalated porphyrin-COF (Ptp-Fe) were synthesized via imine condensation between 5,10,15,20-tetrakis(4-aminophenyl)porphyrin and terephthalaldehyde in the absence and presence of ferric chloride, respectively. The presence of ferric chloride generated both doubly protonated and Fe3+-coordinated porphyrin units, which red-shifted and increased the Q-band absorption and disrupted exciton migration to prevent excited state quenching, respectively. Under light irradiation, rapid energy transfer from protonated porphyrins to Fe3+-coordinated porphyrins in Ptp-Fe enabled 1O2 and hydroxyl radical generation via type II and type I PDT processes. Ptp-Fe also catalyzed the conversion of hydrogen peroxide to hydroxy radical through a photoenhanced Fenton-like reaction under slightly acidic conditions and light illumination. As a result, Ptp-Fe-mediated PDT exhibited much higher cytotoxicity than Ptp-mediated PDT on CT26 and 4T1 cancer cells. Ptp-Fe-mediated PDT afforded potent antitumor efficacy in subcutaneous CT26 murine colon cancer and orthotopic 4T1 murine triple-negative breast tumors and prevented metastasis of 4T1 breast cancer to the lungs. This work underscores the role of fine-tuning the molecular structures of COFs in significantly enhancing their PDT efficacy.

Hollow Cavity CaO2 @Polydopamine Nanocomposites for pH-Responsive Ca2+ -Enhanced Efficient Mild Hyperthermia in the NIR-II Region.

Second near-infrared (NIR-II) mild photothermal therapy with higher tissue penetration depth and less damage to healthy tissues is emerging as an attractive antitumor modality, but its therapeutic efficiency is dramatically suppressed by the resistance of heat shock proteins (HSPs). As a widely explored photothermal agent, the application of polydopamine (PDA) in the NIR-II region is hampered by low photothermal conversion efficiency (PCE). Herein, its PCE in the NIR-II region is improved by developing novel hollow cavity CaO2 @PDA nanocomposites through chelation-induced diffusion of inner core Ca2+ to the shell PDA to facilitate multiple reflections of laser in the cavity. Upon pH-responsive degradation of CaO2 , its structure is transformed into a stacked "nano-mesh" with excellent light absorption and an enlarged effective irradiation area. Overloading of Ca2+ ions not only induces downregulation of HSPs but also enhances interference of light on membrane potential, which further aggravate mitochondrial dysfunction and reduce the thermotolerance of tumor cells, promoting efficient mild hyperthermia of PDA in the NIR-II region.

Mechanoregulatory Cholesterol Oxidase-Functionalized Nanoscale Metal-Organic Framework Stimulates Pyroptosis and Reinvigorates T Cells.

Cancer cells alter mechanical tension in their cell membranes. New interventions to regulate cell membrane tension present a potential strategy for cancer therapy. Herein, the increase of cell membrane tension by cholesterol oxidase (COD) via cholesterol depletion in vitro and the design of a COD-functionalized nanoscale metal-organic framework, Hf-TBP/COD, for cholesterol depletion and mechanoregulation of tumors in vivo, are reported. COD is found to deplete cholesterol and disrupt the mechanical properties of lipid bilayers, leading to decreased cell proliferation, migration, and tolerance to oxidative stress. Hf-TBP/COD increases mechanical tension of plasma membranes and osmotic fragility of cancer cells, which induces influx of calcium ions, inhibits cell migration, increases rupturing propensity for effective caspase-1 mediated pyroptosis, and decreases tolerance to oxidative stress. In the tumor microenvironment, Hf-TBP/COD downregulates multiple immunosuppressive checkpoints to reinvigorate T cells and enhance T cell infiltration. Compared to Hf-TBP, Hf-TBP/COD improves anti-tumor immune response and tumor growth inhibition from 54.3% and 79.8% to 91.7% and 95% in a subcutaneous triple-negative breast cancer model and a colon cancer model, respectively.

Nanoscale Metal-Organic Framework with an X-ray Triggerable Prodrug for Synergistic Radiotherapy and Chemotherapy.

As heavy-metal-based nanoscale metal-organic frameworks (nMOFs) are excellent radiosensitizers for radiotherapy via enhanced energy deposition and reactive oxygen species (ROS) generation, we hypothesize that nMOFs with covalently conjugated and X-ray triggerable prodrugs can harness the ROS for on-demand release of chemotherapeutics for chemoradiotherapy. Herein, we report the design of a novel nMOF, Hf-TP-SN, with an X-ray-triggerable 7-ethyl-10-hydroxycamptothecin (SN38) prodrug for synergistic radiotherapy and chemotherapy. Upon X-ray irradiation, electron-dense Hf12 secondary building units serve as radiosensitizers to enhance hydroxyl radical generation for the triggered release of SN38 via hydroxylation of the 3,5-dimethoxylbenzyl carbonate followed by 1,4-elimination, leading to 5-fold higher release of SN38 from Hf-TP-SN than its molecular counterpart. As a result, Hf-TP-SN plus radiation induces significant cytotoxicity to cancer cells and efficiently inhibits tumor growth in colon and breast cancer mouse models.

Glutathione-Induced In Situ Michael Addition between Nanoparticles for Pyroptosis and Immunotherapy.

Most tumor treatments will fail when ignoring competition and cooperation between each cancer cell and its microenvironment. Inspired by game theory, therapeutic agents can be introduced to compete for intracellular molecules to disrupt the cooperation between molecules and cells. Biomineralized oxidized (-)-epigallocatechin-3-o-gallate (EGCG)-molybdenum ion coordination nanoparticles were prepared for disrupting redox equilibria and simultaneously reacting with intracellular GSH in a Michael addition to form large aggregates that can mechanically disrupt endosomal and plasma membranes, stimulating pyroptosis and anti-tumor immunological responses for versatile inhibition of different types of tumors. This design disrupts the cooperation between molecules and between cancer and immune cells, achieving an optimal payoff in competition and cooperation in cancer therapy.

Nanoparticle-Mediated Radiotherapy Remodels the Tumor Microenvironment to Enhance Antitumor Efficacy.

Radiotherapy (RT) uses ionizing radiation to eradicate localized tumors and, in rare cases, control tumors outside of the irradiated fields via stimulating an antitumor immune response (abscopal effect). However, the therapeutic effect of RT is often limited by inherent physiological barriers of the tumor microenvironment (TME), such as hypoxia, abnormal vasculature, dense extracellular matrix (ECM), and an immunosuppressive TME. Thus, it is critical to develop new RT strategies that can remodel the TME to overcome radio-resistance and immune suppression. In the past decade, high-Z-element nanoparticles have been developed to increase radiotherapeutic indices of localized tumors by reducing X-ray doses and side effects to normal tissues and enhance abscopal effects by activating the TME to elicit systemic antitumor immunity. In this review, the principles of RT and radiosensitization, the mechanisms of radio-resistance and immune suppression, and the use of various nanoparticles to sensitize RT and remodel TMEs for enhanced antitumor efficacy are discussed. The challenges in clinical translation of multifunctional TME-remodeling nanoradiosensitizers are also highlighted.

Generation of singlet oxygen via iron-dependent lipid peroxidation and its role in Ferroptosis.

Ferroptosis is a cell death pathway mediated by iron-dependent accumulation of lipid peroxide. However, the specific downstream molecular events of iron-dependent lipid peroxidation are yet to be elucidated. In this study, based on various spectral analyses, we have found evidence that singlet oxygen is produced through the Russell mechanism during the self-reaction of lipid peroxyl radicals generated via iron-dependent lipid peroxidation regardless of the presence of cholesterol. Significantly reduced generation of singlet oxygen was observed in the absence of iron. The generated singlet oxygen accelerated the oxidative damage of lipid membranes by propagating lipid peroxidation and facilitated ferroptotic cancer cell death initiated by erastin. In this work, singlet oxygen has been revealed to be a new reactive species that participates in ferroptosis, thus improving the understanding on iron-dependent lipid peroxidation and the mechanism of ferroptosis.

Development of Nickel Selenide@polydopamine Nanocomposites for Magnetic Resonance Imaging Guided NIR-II Photothermal Therapy.

The penetration depth of near-infrared laser has greatly restricted the development of most photothermal agents. Recently, photothermal agents in the second near-infrared (NIR-II) window have drawn great attention as they can overcome above barrier. Herein, a novel "all in one" NIR-II responsive nanoplatform (nickel selenide @polydopamine nanocomposites, NiSe@PDA NCs) based on in situ coating the polydopamine (PDA) on the surface of biomineralized nickel selenide nanoparticles (NiSe NPs) for dual-model imaging-guided photothermal therapy is reported. Under the illumination of NIR-II laser (1064 nm), the photothermal conversion efficiency of NiSe@PDA NCs can reach 48.4%, which is higher than that of single NiSe NPs due to the enhanced molar extinction coefficient. In addition, because of the paramagnetic effect of NiSe NPs, the constructed NiSe@PDA NCs can be acted as T1 contrast agent for magnetic resonance imaging (MRI). Most importantly, the MRI contrast effect is enhanced with the coating of PDA layer due to the loose structure of PDA. Ultimately, both in vitro and in vivo experiments demonstrate that the developed NCs can achieve efficient MRI-guided photothermal therapy for treating malignant tumor. Therefore, the designed NiSe@PDA NCs with excellent features show great potential for clinical MRI-guided cancer therapy.

Precise Subcellular Organelle Targeting for Boosting Endogenous-Stimuli-Mediated Tumor Therapy.

Though numerous external-stimuli-triggered tumor therapies, including phototherapy, radiotherapy, and sonodynamic therapy have made great progress in cancer therapy, the low penetration depth of the laser, safety concerns of radiation, the therapeutic resistance, and the spatio-temporal constraints of the specific equipment restrict their convenient clinical applications. What is more, the inherent physiological barriers of the tumor microenvironment (TME), including hypoxia, heterogeneity, and high expression of antioxidant molecules also restrict the efficiency of tumor therapy. As a result, the development of nanoplatforms responsive to endogenous stimuli (such as glucose, acidic pH, cellular redox events, and etc.) has attracted great attention for starvation therapy, ion therapy, prodrug-mediated chemotherapy, or enzyme-catalyzed therapy. In addition, nanomedicines can be modified by some targeted units for precisely locating in subcellular organelles and boosting the destroying of tumor tissue, decreasing the dosage of nanoagents, reducing side effects, and enhancing the therapeutic efficiency. Herein, the properties of the TME, the advantages of endogenous stimuli, and the principles of subcellular-organelle-targeted strategies will be emphasized. Some necessary considerations for the exploitation of precision medicine and clinical translation of multifunctional nanomedicines in the future are also pointed out.

Molecular Nature of Structured Water in the Light-Induced Interfacial Capacitance Changes at the Bioelectric Interface.

Uncovering the function of structured water in the interfacial capacitance at the molecular level is the basis for the development of the concept and model of the electric double layer; however, the limitation of the available technology makes this task difficult. Herein, using surface-enhanced infrared absorption spectroscopy combined with electrochemistry, we revealed the contribution of the cleavage of loosely bonded tetrahedral water to the enhancement of model membrane capacitance. Upon further combination with ionic perturbation, we found that the interface hydrogen bonding environment in the stern layer was greatly significant for the light-induced cleavage of tetrahedral water and thus the conversion of optical signals into electrical signals. Our work has taken an important step toward gaining experimental insight into the relationship between water structure and capacitance at the bioelectric interface.

Na2S2O8 Nanoparticles Trigger Antitumor Immunotherapy through Reactive Oxygen Species Storm and Surge of Tumor Osmolarity.

Although more attention has been attracted to the therapy based on reactive oxygen species (ROS) for tumor therapy in recent years, such as photodynamic therapy and chemodynamic therapy, the limited ROS production rate leads to their poor treatment effect owing to the relatively low content of O2 and H2O2 in tumor microenvironments, confined light penetration depth, strict Fenton reaction conditions (pH 3-4), and so on. Therefore, it is urgent to explore the new agents with highly efficient ROS generation capacity. Herein, we first prepared phospholipid coated Na2S2O8 nanoparticles (PNSO NPs) as new ROS generation agents for in situ generating Na+ and S2O82- through gradual degradation, which can then be changed to toxic •SO4- (a novel reported ROS) and •OH regardless of the amount of H2O2 and pH value in the tumor microenvironment (TME). As the generation of a large amount of Na+, PNSO NPs can bypass the ion transport rules of cells through endocytosis to deliver large amounts of Na+ into the cells, resulting in a surge of osmolarity and rapid cell rupture and lysis. Osmotic pressure induced by PNSO NPs will further lead to an unusual manner of cell death: caspase-1-related pyroptosis. Moreover, all of above effects will cause high immunogenic cell death, regulate the immunosuppressed TME, and then activate systemic antitumor immune responses to combat tumor metastasis and recurrence. We believe PNSO NPs will be new and potential ROS generation agents, and this work will broaden the thinking of the exploring of new antitumor nanodrugs.

Defect modified zinc oxide with augmenting sonodynamic reactive oxygen species generation.

Poor chemical stability, low tumor enrichment, and weak therapeutic effects of commonly used organic sonosensitizers significantly hinder further clinical applications of sonodynamic therapy (SDT). Encouraged by the principles of semiconductor catalysis and defect chemistry, we obtained a defect-rich gadolinium (Gd) doped zinc oxide (D-ZnOx:Gd) semiconductor sonosensitizer by defect engineering for efficient deep tumor sonodynamic eradication. The abundant oxygen defect can promote the separation of the electron (e-) and hole (h+) of D-ZnOx:Gd, which significantly enhances the sonodynamic effect. In addition, D-ZnOx:Gd is more easier to adsorb water and oxygen molecules due to its rich oxygen-deficient, greatly enhancing the capacities of ROS production. A significantly higher sonodynamic ROS generation abilities and anti-deep tumor efficiency against breast cancer are obtained in such defect-rich ZnO nanobullets. This work not only broadens the applications of ZnO semiconductor nanoagent in the field of nanomedicine, but also reveals the mechanism of how the oxygen deficiency enhanced the sonodynamic efficacy of zinc oxide, providing a new application of defect engineering in the field of cancer therapy.

Specific "Unlocking" of a Nanozyme-Based Butterfly Effect To Break the Evolutionary Fitness of Chaotic Tumors.

Chaos and the natural evolution of tumor systems can lead to the failure of tumor therapies. Herein, we demonstrate that iridium oxide nanoparticles (IrOx ) possess acid-activated oxidase and peroxidase-like functions and wide pH-dependent catalase-like properties. The integration of glucose oxidase (GOD) unlocked the oxidase and peroxidase activities of IrOx by the production of gluconic acid from glucose by GOD catalysis in cancer cells, and the produced H2 O2 was converted into O2 to compensate its consumption in GOD catalysis owing to the catalase-like function of the nanozyme, thus resulting in the continual consumption of glucose and the self-supply of substrates to generate superoxide anion and hydroxyl radical. Moreover, IrOx can constantly consume glutathione (GSH) by self-cyclic valence alternation of IrIV and IrIII . These cascade reactions lead to a "butterfly effect" of initial starvation therapy and the subsequent pressure of multiple reactive oxygen species (ROS) to completely break the self-adaption of cancer cells.

Nanomaterials for the regulation of the tumor microenvironment and theranostics.

Cancer has become one of the primary threats to human beings, and traditional therapies (including surgery, chemotherapy and radiotherapy) show limited therapeutic efficacy due to the complexity of tumor biology. Furthermore, determining how to utilize the differences between the tumor microenvironment (TME) and healthy tissues and exploring new nanoplatforms that can realize early diagnosis and effective and non-toxic therapy are challenges in cancer theranostics. Numerous researchers have designed multifunctional nanomaterials and investigated their personalized therapy and regulation abilities toward TME, including oxygen generation, glutathione consumption and the production of reactive oxygen species and multi-model imaging effects. This review will introduce the latest progress in the design of multi-functional nanomedicines for the regulation of TME and their theranostics, and it will provide a critical angle for the future development of nanomedicine.

Biodegradable iron-coordinated hollow polydopamine nanospheres for dihydroartemisinin delivery and selectively enhanced therapy in tumor cells.

As the semisynthetic derivative and active metabolite of the effective anti-malarial drug artemisinin, dihydroartemisinin (DHA) has been investigated as an emerging therapeutic agent for tumor treatment based on the cytotoxicity of free-radicals originating from interactions with ferrous ions. Meanwhile, simultaneously delivering DHA and iron ions to tumors for selectively killing cancer cells is still a great challenge in DHA tumor therapy. Herein, we develop a facile yet efficient strategy based on iron-coordinated hollow polydopamine nanospheres to load DHA (DHA@HPDA-Fe). The as-prepared nanoagent is biodegradable and exhibits controllable release of DHA and Fe ions in tumor microenvironments, resulting in ferrous ion-enhanced production of cytotoxic reactive oxygen species (ROS) by DHA and thus effectively killing the tumor cells. In vivo therapy experiments indicated that the anti-tumor efficacy of DHA@HPDA-Fe was about 3.05 times greater than that of free DHA, and the tumor inhibition ratio was 88.7% compared with the control group, accompanied by negligible side effects, indicating that the proposed nanomedicine platform is promising for anti-tumor applications.

Double Switch Biodegradable Porous Hollow Trinickel Monophosphide Nanospheres for Multimodal Imaging Guided Photothermal Therapy.

Due to the limitation of inorganic nanomaterials in present clinical applications induced by their inherent nonbiodegradability and latent long-term side effects, we successfully prepared double switch degradable and clearable trinickel monophosphide porous hollow nanospheres (NiP PHNPs) modified with bovine serum albumin (BSA). Attributed to their acidic and oxidative double switch degradation capacities, NiP PHNPs can be effectively excreted from mice without long-term toxicity. Moreover, because of the paramagnetic and high molar extinction coefficient property resulting from the strong absorption in the second near-infrared light (NIR II) biowindow, NiP PHNPs have potential to be used for photoacoustic imaging (PAI) and T1-weighted magnetic resonance imaging (MRI) guided photothermal ablation of tumors in the NIR II biowindow. Specifically, it is interesting that the hollow structure and acidic degradation property enable NiP PHNPs to act as intelligent drug carriers with an on-demand release ability. These findings highlight the great potential of NiP PHNPs in the cancer theranostics field and inspire us to further broaden the bioapplications of transition metal phosphides.

Gram-scale fabrication of Bi@C nanoparticles through one-step hydrothermal method for dual-model imaging-guided NIR-II photothermal therapy.

At present, increasing attention is being paid to photothermal therapy corresponding to the second near infrared (NIR-II) range (1000-1700 nanometers); however, its biomedical applications related to carbon-based nanomaterials (CNMs) have always been limited by the large-scale fabrication of excellent diagnostic probes with a suitable size and optical absorption cross-section. Herein, we successfully prepared Bi@C nanoparticles with a suitable size and high output (3.14 g per patch) through a one-pot hydrothermal method. By combining Bi with carbon, the optical absorption in the NIR-II range was enhanced compared to that for single carbon; moreover, Bi@C could no longer be easily oxidized due to the protection of outer C compared with individual Bi. Furthermore, because of the high atomic number of Bi (Z = 83), the Bi@C nanoparticles exhibited computed imaging contrast properties. According to the in vitro and in vivo experiments, the Bi@C nanoparticles could ablate cancer cells under illumination with a 1064 nm laser with deeper penetration and an appropriate permissible exposure (MPE) to the laser (1 W cm-2), showing excellent performance for the diagnosis and treatment of tumors. This study provides a simple method to synthesize metal-carbon nanocomposites to enhance the NIR-II optical absorption efficiency for effective deep-seated tumor photothermal therapy and will further broaden the applications of CNMs.

Specific Generation of Singlet Oxygen through the Russell Mechanism in Hypoxic Tumors and GSH Depletion by Cu-TCPP Nanosheets for Cancer Therapy.

The generation of singlet oxygen (1 O2 ) during photodynamic therapy is limited by the precise cooperation of light, photosensitizer, and oxygen, and the therapeutic efficiency is restricted by the elevated glutathione (GSH) levels in cancer cells. Herein, we report that an ultrathin two-dimensional metal-organic framework of Cu-TCPP nanosheets (TCPP=tetrakis(4-carboxyphenyl)porphyrin) can selectively generate 1 O2 in a tumor microenvironment. This process is based on the peroxidation of the TCPP ligand by acidic H2 O2 followed by reduction to peroxyl radicals under the action of the peroxidase-like nanosheets and Cu2+ , and their spontaneous recombination reaction by the Russell mechanism. In addition, the nanosheets can also deplete GSH. Consequently, the Cu-TCPP nanosheets can selectively destroy tumor cells with high efficiency, constituting an attractive way to overcome current limitations of photodynamic therapy.

One-Dimensional Fe2 P Acts as a Fenton Agent in Response to NIR†II Light and Ultrasound for Deep Tumor Synergetic Theranostics.

The stringent reaction conditions for an effective Fenton reaction (pH range of 3-4) hinders its application in cancer therapy. Therefore, how to improve the efficiency of the Fenton reaction in a tumor site has been the main obstacle in chemodynamic therapy (CDT). Herein, we report biocompatible one-dimensional (1D) ferrous phosphide nanorods (FP NRs) with ultrasound (US)- and photothermal (PT)-enhanced Fenton properties and excellent photothermal conversion efficiency (56.6 %) in the NIR II window, showing synergistic therapeutic properties. Additionally, the high photothermal conversion efficiency and excellent traverse relaxivity (277.79 mm-1 s-1 ) of the FP NRs means they are excellent photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) agents. This is the first report on exploiting the response of metallic phosphides to NIR II laser (1064 nm) and ultrasound to improve the CDT effect with a high therapeutic effect and PA/MR imaging.