Computed Tomography Imaging Guided Microenvironment-Responsive Ir@WO3-x Dual-Catalytic Nanoreactor for Selective Radiosensitization.

Radiotherapy (RT) is often administered, either alone or in combination with other therapies, for most malignancies. However, the degree of tumor oxygenation, damage to adjacent healthy tissues, and inaccurate guidance remain issues that result in discontinuation or failure of RT. Here, a multifunctional therapeutic platform based on Ir@WO3-x is developed which simultaneously addresses these critical issues above for precision radiosensitization. Ir@WO3-x nanoreactors exhibit strong absorption of X-ray, acting as radiosensitizers. Moreover, ultrasmall Ir enzyme-mimic nanocrystals (NCs) are decorated onto the surface of the nanoreactor, where NCs have catalyst-like activity and are sensitive to H2O2 in the tumor microenvironment (TME) under near infrared-II (NIR-II) light stimulation. They efficiently catalyze the conversion of H2O2 to O2, thereby ameliorating hypoxia, inhibiting the expression of HIF-1α, and enhancing RT-induced DNA damage in cancerous tissue, further improving the efficiency of RT. Additionally, in response to high H2O2 levels in TME, the Ir@WO3-x nanoreactor also exerts peroxidase-like activity, boosting exogenous ROS, which increases oxidative damage and enhances ROS-dependent death signaling. Furthermore, Ir@WO3-x can serve as a high-quality computed tomography contrast agent due to its high X-ray attenuation coefficient and generation of pronounced tumor-tissue contrast. This report highlights the potential of advanced health materials to enhance precision therapeutic modalities.

Nanozyme: a rising star for cancer therapy.

In recent years, nanozymes have attracted enormous attention due to their effectiveness in promoting various catalytic reactions. To date, thousands of nanozymes have been discovered, including oxidase-like nanozymes, peroxidase-like nanozymes, and catalase-like nanozymes, covering noble metal, transition metal, and carbon nanomaterials. These nanozymes have been widely applied in various fields, including environmental protection, biosensing and nanomedicine. There are many reviews about this rising star being used in analytical chemistry. However, few works about nanozymes were related to cancer therapy. In this study, we comprehensively summarize the latest research advances on the strategies for cancer therapy based on different nanozymes. With traditional cancer treatment (including chemotherapy, radiotherapy, phototherapy), nanozyme catalytic therapy exhibited a synergistic effect for limiting the growth of tumors. Opportunities and trends for nanozymes in future cancer therapy are also discussed.

Unexcited Light Source Imaging for Biomedical Applications.

Optical imaging has a wide range of applications in the biomedical field, allowing the visualization of physiological processes and helping in the diagnosis and treatment of diseases. Unexcited light source imaging technologies, such as chemiluminescence imaging, bioluminescence imaging and afterglow imaging have attracted great attention in recent years because of the absence of excitation light interference in their application and the advantages of high sensitivity and high signal-to-noise ratio. In this review, the latest advances in unexcited light source imaging technology for biomedical applications are highlighted. The design strategies of unexcited light source luminescent probes in improving luminescence brightness, penetration depth, quantum yield and targeting, and their applications in inflammation imaging, tumor imaging, liver and kidney injury imaging and bacterial infection imaging are introduced in detail. The research progress and future prospects of unexcited light source imaging for medical applications are further discussed.

Engineered Toll-like Receptor Nanoagonist Binding to Extracellular Matrix Elicits Safe and Robust Antitumor Immunity.

Cancer immunotherapy, such as the Toll-like receptor (TLR) agonist including CpG oligodeoxynucleotide, has shown potency in clinical settings. However, it is still confronted with multiple challenges, which include the limited efficacy and severe adverse events caused by the rapid clearance and systemic diffusion of CpG. Here we report an improved CpG-based immunotherapy approach composed of a synthetic extracellular matrix (ECM)-anchored DNA/peptide hybrid nanoagonist (EaCpG) via (1) a tailor designed DNA template that encodes tetramer CpG and additional short DNA moieties, (2) generation of elongated multimeric CpG through rolling circle amplification (RCA), (3) self-assembly of densely packaged CpG particles composed of tandem CpG building blocks and magnesium pyrophosphate, and (4) incorporation of multiple copies of ECM binding peptide through hybridization to short DNA moieties. The structurally well-defined EaCpG shows dramatically increased intratumoral retention and marginal systemic dissemination through peritumoral administration, leading to potent antitumor immune response and subsequent tumor elimination, with minimal treatment-related toxicity. Combined with conventional standard-of-care therapies, peritumor administration of EaCpG generates systemic immune responses that lead to a curative abscopal effect on distant untreated tumors in multiple cancer models, which is superior to the unmodified CpG. Taken together, EaCpG provides a facile and generalizable strategy to simultaneously potentiate the potency and safety of CpG for combinational cancer immunotherapies.

Research Status and Prospect of Non-Viral Vectors Based on siRNA: A Review.

Gene therapy has attracted much attention because of its unique mechanism of action, non-toxicity, and good tolerance, which can kill cancer cells without damaging healthy tissues. siRNA-based gene therapy can downregulate, enhance, or correct gene expression by introducing some nucleic acid into patient tissues. Routine treatment of hemophilia requires frequent intravenous injections of missing clotting protein. The high cost of combined therapy causes most patients to lack the best treatment resources. siRNA therapy has the potential of lasting treatment and even curing diseases. Compared with traditional surgery and chemotherapy, siRNA has fewer side effects and less damage to normal cells. The available therapies for degenerative diseases can only alleviate the symptoms of patients, while siRNA therapy drugs can upregulate gene expression, modify epigenetic changes, and stop the disease. In addition, siRNA also plays an important role in cardiovascular diseases, gastrointestinal diseases, and hepatitis B. However, free siRNA is easily degraded by nuclease and has a short half-life in the blood. Research has found that siRNA can be delivered to specific cells through appropriate vector selection and design to improve the therapeutic effect. The application of viral vectors is limited because of their high immunogenicity and low capacity, while non-viral vectors are widely used because of their low immunogenicity, low production cost, and high safety. This paper reviews the common non-viral vectors in recent years and introduces their advantages and disadvantages, as well as the latest application examples.

Responsive Accumulation of Nanohybrids to Boost NIR-Phototheranostics for Specific Tumor Imaging and Glutathione Depletion-Enhanced Synergistic Therapy.

Dynamic regulation of nanoparticles in a controllable manner has great potential in various areas. Compared to the individual nanoparticles, the assembled nanoparticles exhibit superior properties and functions, which can be applied to achieve desirable performances. Here, a pH-responsive i-motif DNA-mediated strategy to tailor the programmable behaviors of erbium-based rare-earth nanoparticles (ErNPs) decorated copper doped metal-organic framework (CPM) nanohybrids (ECPM) under physiological conditions is reported. Within the acidic tumor microenvironment, the i-motif DNA strands are able to form quadruplex structures, resulting in the assembly of nanohybrids and selective tumor accumulation, which further amplify the ErNPs downconversion emission (1550 nm) signal for imaging. Meanwhile, the ECPM matrix acts as a near-infrared (NIR) photon-activated reactive oxygen species (ROS) amplifier through the singlet oxygen generation of the matrix in combination with its ability of intracellular glutathione depletion upon irradiation. In short, this work displays a classical example of engineering of nanoparticles, which will manifest the importance of developing nanohybrids with structural programmability in biomedical applications.

Recent advances in nanotechnology mediated mitochondria-targeted imaging.

Mitochondria play a critical role in cell growth and metabolism. And mitochondrial dysfunction is closely related to various diseases, such as cancers, and neurodegenerative and cardiovascular diseases. Therefore, it is of vital importance to monitor mitochondrial dynamics and function. One of the most widely used methods is to use nanotechnology-mediated mitochondria targeting and imaging. It has gained increasing attention in the past few years because of the flexibility, versatility and effectiveness of nanotechnology. In the past few years, researchers have implemented various types of design and construction of the mitochondrial structure dependent nanoprobes following assorted nanotechnology pathways. This review presents an overview on the recent development of mitochondrial structure dependent target imaging probes and classifies it into two main sections: mitochondrial membrane targeting and mitochondrial microenvironment targeting. Also, the significant impact of previous research as well as the application and perspectives will be demonstrated.

Ultrasound improved immune adjuvant delivery to induce DC maturation and T cell activation.

Tumor immunotherapy has emerged as a promising approach to tumor treatment. Currently, immune adjuvant-based therapeutic modalities are rarely curative in solid tumors owing to challenges including the low permeability and extremely poor water solubility of these adjuvants, limiting their ability to effectively promote dendritic cell (DC) maturation. Herein, we employed ultrasound-mediated cavitation (UMC) to promote the delivery of Toll-like receptor agonist (R837)-loaded pH-responsive liposomes (PEOz-Lip@R837) to tumors. The tumor-associated antigens (TAAs) produced by UMC treatment exhibited vaccinal activity, particularly in the presence of immune adjuvants, together promoting the maturation of DC and inducing cytokine production. Importantly, UMC can down-regulate immune checkpoint molecules, like Cd274, Foxp3 and Ctla4, synergistically stimulating the activation and proliferation of T cells in the body to facilitate tumor treatment. This UMC-enhanced PEOz-Lip@R837 approach was able to induce a robust antitumor immune response capable of arresting primary and distant tumor growth, while also developing immunological memory, protecting against tumor rechallenge following initial tumor clearance. Overall, these results highlight a promising UMC- and pH-sensitive immune adjuvant delivery-based treatment for tumors with the potential for clinical application.

Protective effect of platinum nano-antioxidant and nitric oxide against hepatic ischemia-reperfusion injury.

Therapeutic interventions of hepatic ischemia-reperfusion injury to attenuate liver dysfunction or multiple organ failure following liver surgery and transplantation remain limited. Here we present an innovative strategy by integrating a platinum nanoantioxidant and inducible nitric oxide synthase into the zeolitic imidazolate framework-8 based hybrid nanoreactor for effective prevention of ischemia-reperfusion injury. We show that platinum nanoantioxidant can scavenge excessive reactive oxygen species at the injury site and meanwhile generate oxygen for subsequent synthesis of nitric oxide under the catalysis of nitric oxide synthase. We find that such cascade reaction successfully achieves dual protection for the liver through reactive oxygen species clearance and nitric oxide regulation, enabling reduction of oxidative stress, inhibition of macrophage activation and neutrophil recruitment, and ensuring suppression of proinflammatory cytokines. The current work establishes a proof of concept of multifunctional nanotherapeutics against ischemia-reperfusion injury, which may provide a promising intervention solution in clinical use.

Enhancement of antitumor immunotherapy using mitochondria-targeted cancer cell membrane-biomimetic MOF-mediated sonodynamic therapy and checkpoint blockade immunotherapy.

Immunotherapeutic interventions represent a promising approach to treating cancer, with strategies such as immune checkpoint blockade (ICB), immunogenic sonodynamic therapy (SDT), and immune adjuvant T cell delivery having exhibited clinical promise. In this report, we describe the use of cancer cell membrane-coated triphenylphosphonium (TPP) decorated nano-metal-organic framework (nMOF) constructs [Zr-TCPP(TPP)/R837@M] that were used to generate homologous, mitochondria-targeted platforms with a high rate of sonosensitizer loading. This construct was utilized to simultaneously promote tumor antigen presentation via enhancing SDT while synergistically promoting dendritic cell (DC) maturation through the delivery of the Toll-like receptor agonist R837. In vitro, these functionalized nMOFs were readily internalized by homologous tumor cells in which they were efficiently targeted to the mitochondria, promoting DC activation through the induction of immunogenic cell death (ICD) following ultrasound exposure. Moreover, this nanoplatform was able to achieve in vivo synergy with anti-CTLA-4 ICB to reverse immunosuppression tumor microenvironment (TME), thus achieving more robust antitumor efficacy capable of suppressing metastatic disease progression and facilitating the development of durable antitumor memory responses. Together, these results highlight a promising approach to achieving enhanced SDT activity while overcoming an immunosuppressive TME, thereby achieving more robust antitumor immunity.

Targeting the innate immune system with nanoparticles for cancer immunotherapy.

Various cancer therapies have advanced remarkably over the past decade. Unlike the direct therapeutic targeting of tumor cells, cancer immunotherapy is a new strategy that boosts the host's immune system to detect specific cancer cells for efficient elimination. Unfortunately, the efficacy of these treatments has been limited to a fraction of patients within a subset of tumor types, and further studies are still needed to clarify these mechanisms and develop novel approaches to improve the efficacy of cancer immunotherapy. Emerging data suggest that the innate immune system also plays a key role in tumor immunosurveillance and generation of antitumor immune responses. Nanoparticles incorporating immunomodulatory agents can activate immune cells and modulate the tumor microenvironment to enhance antitumor immunity. Such nanoparticle-based cancer immunotherapies have received considerable attention and have been extensively studied in recent years. In this review, we will discuss the anticancer activities of nanoparticles designed to target innate immune pathways, including Toll-like receptor, nucleotide-binding oligomerization domain-like receptor, and retinoic acid-inducible gene-I-like receptor pathways, as well as DNA sensing pathways. In addition, nanoparticles that target key innate immune cell types, such as macrophages, myeloid-derived suppressor cells, dendritic cells, natural killer cells, and neutrophils, also will be investigated. In summary, although further research and clinical studies are still needed to solve the safety concerns and improve the efficacy of nanoplatform-based cancer immunotherapy, the recent studies presented in this review prove that nanoparticle-incorporated cancer immunotherapy is a highly promising treatment for cancer patients.

Biodegradable Metal-Organic-Framework-Gated Organosilica for Tumor-Microenvironment-Unlocked Glutathione-Depletion-Enhanced Synergistic Therapy.

The clinical employment of cisplatin (cis-diamminedichloroplatinum(II) (CDDP)) is largely constrained due to the non-specific delivery and resultant serious systemic toxicity. Small-sized biocompatible and biodegradable hollow mesoporous organosilica (HMOS) nanoparticles show superior advantages for targeted CDDP delivery but suffer from premature CDDP leakage. Herein, the smart use of a bimetallic Zn2+ /Cu2+ co-doped metal-organic framework (MOF) is made to block the pores of HMOS for preventing potential leakage of CDDP and remarkably increasing the loading capacity of HMOS. Once reaching the acidic tumor microenvironment (TME), the outer MOF can decompose quickly to release CDDP for chemotherapy against cancer. Besides, the concomitant release of dopant Cu2+ can deplete the intracellular glutathione (GSH) for increased toxicity of CDDP as well as catalyzing the decomposition of intratumoral H2 O2 into highly toxic •OH for chemodynamic therapy (CDT). Moreover, the substantially reduced GSH can also protect the yielded •OH from scavenging and thus greatly improve the •OH-based CDT effect. In addition to providing a hybrid HMOS@MOF nanocarrier, this study is also expected to establish a new form of TME-unlocked nanoformula for highly efficient tumor-specific GSH-depletion-enhanced synergistic chemotherapy/chemodynamic therapy.

Biphasic synthesis of biodegradable urchin-like mesoporous organosilica nanoparticles for enhanced cellular internalization and precision cascaded therapy.

It is widely accepted that a small particle size and rough surface can enhance tumor tissue accumulation and tumor cellular uptake of nanoparticles, respectively. Herein, sub-50 nm urchin-inspired disulfide bond-bridged mesoporous organosilica nanoparticles (UMONs) featured with a spiky surface and glutathione (GSH)-responsive biodegradability were successfully synthesized by a facile one-pot biphasic synthesis strategy for enhanced cellular internalization and tumor accumulation. l-Arginine (LA) is encapsulated into the mesopores of UMONs, whose outer surface is capped with the gatekeeper of ultrasmall gold nanoparticles, i.e., UMONs-LA-Au. On the one hand, the mild acidity-activated uncapping of ultrasmall gold can realize a tumor microenvironment (TME)-responsive release of LA. On the other hand, the unique natural glucose oxidase (GOx)-mimicking catalytic activity of ultrasmall gold can catalyze the decomposition of intratumoral glucose to produce acidic hydrogen peroxide (H2O2) and gluconic acid. Remarkably, these products can not only further facilitate the release of LA, but also catalyze the LA-H2O2 reaction for an increased nitric oxide (NO) yield, which realizes synergistic catalysis-enhanced NO gas therapy for tumor eradication. The judiciously fabricated UMONs-LA-Au present a paradigm of TME-responsive nanoplatforms for both enhanced cellular uptake and tumor-specific precision cascaded therapy, which broadens the range of practical biomedical applications and holds a significant promise for the clinical translation of silica-based nanotheranostics.

A hybrid semiconducting organosilica-based O2 nanoeconomizer for on-demand synergistic photothermally boosted radiotherapy.

The outcome of radiotherapy is significantly restricted by tumor hypoxia. To overcome this obstacle, one prevalent solution is to increase intratumoral oxygen supply. However, its effectiveness is often limited by the high metabolic demand for O2 by cancer cells. Herein, we develop a hybrid semiconducting organosilica-based O2 nanoeconomizer pHPFON-NO/O2 to combat tumor hypoxia. Our solution is twofold: first, the pHPFON-NO/O2 interacts with the acidic tumor microenvironment to release NO for endogenous O2 conservation; second, it releases O2 in response to mild photothermal effect to enable exogenous O2 infusion. Additionally, the photothermal effect can be increased to eradicate tumor residues with radioresistant properties due to other factors. This "reducing expenditure of O2 and broadening sources" strategy significantly alleviates tumor hypoxia in multiple ways, greatly enhances the efficacy of radiotherapy both in vitro and in vivo, and demonstrates the synergy between on-demand temperature-controlled photothermal and oxygen-elevated radiotherapy for complete tumor response.

Size-transformable antigen-presenting cell-mimicking nanovesicles potentiate effective cancer immunotherapy.

Artificial antigen-presenting cells (aAPCs) can stimulate CD8+ T cell activation. While nanosized aAPCs (naAPCs) have a better safety profile than microsized (maAPCs), they generally induce a weaker T cell response. Treatment with aAPCs alone is insufficient due to the lack of autologous antigen-specific CD8+ T cells. Here, we devised a nanovaccine for antigen-specific CD8+ T cell preactivation in vivo, followed by reactivation of CD8+ T cells via size-transformable naAPCs. naAPCs can be converted to maAPCs in tumor tissue when encountering preactivated CD8+ T cells with high surface redox potential. In vivo study revealed that naAPC's combination with nanovaccine had an impressive antitumor efficacy. The methodology can also be applied to chemotherapy and photodynamic therapy. Our findings provide a generalizable approach for using size-transformable naAPCs in vivo for immunotherapy in combination with nanotechnologies that can activate CD8+ T cells.

Reactive Oxygen Species Activatable Heterodimeric Prodrug as Tumor-Selective Nanotheranostics.

Nanotheranostics based on tumor-selective small molecular prodrugs could be more advantageous in clinical translation for cancer treatment, given its defined chemical structure, high drug loading efficiency, controlled drug release, and reduced side effects. To this end, we have designed and synthesized a reactive oxygen species (ROS)-activatable heterodimeric prodrug, namely, HRC, and nanoformulated it for tumor-selective imaging and synergistic chemo- and photodynamic therapy. The prodrug consists of the chemodrug camptothecin (CPT), the photosensitizer 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH), and a thioketal linker. Compared to CPT- or HPPH-loaded polymeric nanoparticles (NPs), HRC-loaded NPs possess higher drug loading capacity, better colloidal stability, and less premature drug leakage. Interestingly, HRC NPs were almost nonfluorescent due to the strong π-π stacking and could be effectively activated by endogenous ROS once entering cells. Thanks to the higher ROS levels in cancer cells than normal cells, HRC NPs could selectively light up the cancer cells and exhibit much more potent cytotoxicity to cancer cells. Moreover, HRC NPs demonstrated highly effective tumor accumulation and synergistic tumor inhibition with reduced side effects on mice.

Activating Macrophage-Mediated Cancer Immunotherapy by Genetically Edited Nanoparticles.

Immunomodulation of macrophages against cancer has emerged as an encouraging therapeutic strategy. However, there exist two major challenges in effectively activating macrophages for antitumor immunotherapy. First, ligation of signal regulatory protein alpha (SIRPα) on macrophages to CD47, a "don't eat me" signal on cancer cells, prevents macrophage phagocytosis of cancer cells. Second, colony stimulating factors, secreted by cancer cells, polarize tumor-associated macrophages (TAMs) to a tumorigenic M2 phenotype. Here, it is reported that genetically engineered cell-membrane-coated magnetic nanoparticles (gCM-MNs) can disable both mechanisms. The gCM shell genetically overexpressing SIRPα variants with remarkable affinity efficiently blocks the CD47-SIRPα pathway while the MN core promotes M2 TAM repolarization, synergistically triggering potent macrophage immune responses. Moreover, the gCM shell protects the MNs from immune clearance; and in turn, the MN core delivers the gCMs into tumor tissues under magnetic navigation, effectively promoting their systemic circulation and tumor accumulation. In melanoma and breast cancer models, it is shown that gCM-MNs significantly prolong overall mouse survival by controlling both local tumor growth and distant tumor metastasis. The combination of cell-membrane-coating nanotechnology and genetic editing technique offers a safe and robust strategy in activating the body's immune responses for cancer immunotherapy.

In Situ Polymerized Hollow Mesoporous Organosilica Biocatalysis Nanoreactor for Enhancing ROS-Mediated Anticancer Therapy.

The combination of reactive oxygen species (ROS)-involved photodynamic therapy (PDT) and chemodynamic therapy (CDT) holds great promise for enhancing ROS-mediated cancer treatment. Herein, we reported an in situ polymerized hollow mesoporous organosilica nanoparticle (HMON) biocatalysis nanoreactor to integrate the synergistic effect of PDT/CDT for enhancing ROS-mediated pancreatic ductal adenocarcinoma treatment. HPPH photosensitizer was hybridized within the framework of HMON via an "in situ framework growth" approach. Then, the hollow cavity of HMONs was exploited as a nanoreactor for "in situ polymerization" to synthesize the polymer containing thiol groups, thereby enabling the immobilization of ultrasmall gold nanoparticles, which behave like glucose oxidase-like nanozyme, converting glucose into H2O2 to provide self-supplied H2O2 for CDT. Meanwhile, Cu2+-tannic acid complexes were further deposited on the surface of HMONs (HMON-Au@Cu-TA) to initiate Fenton-like reaction to covert the self-supplied H2O2 into •OH, a highly toxic ROS. Finally, collagenase (Col), which can degrade the collagen I fiber in the extracellular matrix (ECM), was loaded into HMON-Au@Cu-TA to enhance the penetration of HMONs and O2 infiltration for enhanced PDT. This study provides a good paradigm for enhancing ROS-mediated anti-tumor efficacy. Meanwhile, this research offers a new method to broaden the application of silica based nanotheranostics.

Cascade Reactions Catalyzed by Planar Metal-Organic Framework Hybrid Architecture for Combined Cancer Therapy.

Chemical transformation in cellular environment is critical for regulating biological processes and metabolic pathways. Harnessing biocatalytic cascades to produce chemicals of interest has become a research focus to benefit industrial and pharmaceutic areas. Nanoreactors, which can act as artificial cell-like devices to organize cascade reactions, have been recently proposed for potential therapeutic applications for life-threatening illnesses. Among various types of nanomaterials, there is a growing interest in 2D metal-organic frameworks (MOFs). By virtue of the ultralarge specific surface area, high porosity, and structural diversity, 2D MOF nanosheets hold great promise for a broad spectrum of biomedical use. Herein, a unique planar MOF-based hybrid architecture (GMOF-LA) is introduced by incorporating ultrasmall gold nanoparticles (Au NPs) as nanozyme and l-Arginine (l-Arg) as nitric oxide (NO) donor. The prepared Au NPs enable oxidation of glucose into hydrogen peroxide, which drives biocatalytic cascades to covert l-Arg into NO. Interestingly, the well-designed nanosheets not only possess excellent catalytical activity for NO generation, resulting in gas therapeutic effect, but also serve as a desired photosensitizer for photodynamic therapy. This study establishes a good example of exploring bioinspired nanoreactors for cooperative anticancer effect, which may pave the path for future "bench-to-bedside" design of nanomedicine.