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.

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.

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.

Solvent-Assisted Self-Assembly of a Metal-Organic Framework Based Biocatalyst for Cascade Reaction Driven Photodynamic Therapy.

Biocatalytic reactions in living cells involve complex transformations in the spatially confined microenvironments. Inspired by biological transformation processes, we demonstrate effective biocatalytic cascade driven photodynamic therapy in tumor-bearing mice by the integration of an artificial enzyme (ultrasmall Au nanoparticles) with upconversion nanoparticles (NaYF4@NaYb0.92F4:Er0.08@NaYF4)zirconium/iron porphyrin metal-organic framework core-shell nanoparticles (UMOF NPs) which act as biocatalysts and nanoreactors. The construction of core-shell UMOF NPs are realized by using a unique "solvent-assisted self-assembly" method. The integration of ultrasmall AuNPs on the UMOFs matrix leads to glucose depletion, providing Au-mediated cancer therapy via glucose oxidase like catalytic activity. Meanwhile, the UMOF matrix acts as a near-infrared (NIR) light photon-activated singlet oxygen generator through a continuous supply of oxygen via hydrogen peroxide decomposition upon irradiation. Such kinds of biocatalysts offer exciting opportunities for biomedical, catalytical ,and energy applications.

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.

A Phototheranostic Strategy to Continuously Deliver Singlet Oxygen in the Dark and Hypoxic Tumor Microenvironment.

Continuous irradiation during photodynamic therapy (PDT) inevitably induces tumor hypoxia, thereby weakening the PDT effect. In PDT-induced hypoxia, providing singlet oxygen from stored chemical energy may enhance the cell-killing effect and boost the therapeutic effect. Herein, we present a phototheranostic (DPPTPE@PEG-Py NPs) prepared by using a 2-pyridone-based diblock polymer (PEG-Py) to encapsulate a semiconducting, heavy-atom-free pyrrolopyrrolidone-tetraphenylethylene (DPPTPE) with high singlet-oxygen-generation ability both in dichloromethane and water. The PEG-Py can trap the 1 O2 generated from DPPTPE under laser irradiation and form a stable intermediate of endoperoxide, which can then release 1 O2 in the dark, hypoxic tumor microenvironment. Furthermore, fluorescence-imaging-guided phototherapy demonstrates that this phototheranostic could completely inhibit tumor growth with the help of laser irradiation.

Precision Cancer Theranostic Platform by In Situ Polymerization in Perylene Diimide-Hybridized Hollow Mesoporous Organosilica Nanoparticles.

Phototheranostics refers to advanced photonics-mediated theranostic methods for cancer and includes imaging-guided photothermal/chemotherapy, photothermal/photodynamic therapy, and photodynamic/chemotherapy, which are expected to provide a paradigm of modern precision medicine. In this regard, various phototheranostic drug delivery systems with excellent photonic performance, controlled drug delivery/release, and precise photoimaging guidance have been developed. In this study, we reported a special "in situ framework growth" method to synthesize novel phototheranostic hollow mesoporous nanoparticles by ingenious hybridization of perylene diimide (PDI) within the framework of small-sized hollow mesoporous organosilica (HMO). The marriage of PDI and HMO endowed the phototheranostic silica nanoparticles (HMPDINs) with largely amplified fluorescence and photoacoustic signals, which can be used for enhanced fluorescence and photoacoustic imaging. The organosilica shell can be chemically chelated with isotope 64Cu for positron emission tomography imaging. Moreover, in situ polymer growth was introduced in the hollow structure of the HMPDINs to produce thermosensitive polymer (TP) in the cavity of HMPDINs to increase the loading capacity and prevent unexpected leakage of the hydrophobic drug SN38. Furthermore, the framework-hybridized PDI generated heat under near-infrared laser irradiation to trigger the deformation of TP for controlled drug release in the tumor region. The fabricated hybrid nanomedicine with organic-inorganic characteristic not only increases the cancer theranostic efficacy but also offers an attractive solution for designing powerful theranostic platforms.

Engineering of Nanoscale Coordination Polymers with Biomolecules for Advanced Applications.

Nanoscale coordination polymers (NCPs) have shown extraordinary advantages in various research areas due to their structural diversity and multifunctionality. Recently, integration of biomolecules with NCPs received extensive attention and the formed hybrid materials exhibit superior properties over the individual NCPs or biomolecules. In this review, the state-of-the-art of approaches to engineer NCPs with different types of guest biomolecules, such as amino acids, nucleic acids, enzymes and lipids are systematically introduced. Additionally, advanced applications of these biomolecule-NCP composites in the areas of sensing, catalysis, molecular imaging and therapy are thoroughly summarized. Finally, current challenges and prospects are also discussed.

Anti-EGFR Affibodies with Site-Specific Photo-Cross-Linker Incorporation Show Both Directed Target-Specific Photoconjugation and Increased Retention in Tumors.

A significant challenge for solid tumor treatment is ensuring that a sufficient concentration of therapeutic agent is delivered to the tumor site at doses that can be tolerated by the patient. Biomolecular targeting can bias accumulation in tumors by taking advantage of specific interactions with receptors overexpressed on cancerous cells. However, while antibody-based immunoconjugates show high binding to specific cells, their low dissociation constants ( KD) and large Stokes radii hinder their ability to penetrate deep into tumor tissue, leading to incomplete cell killing and tumor recurrence. To address this, we demonstrate the design and production of a photo-cross-linkable affibody that can form a covalent bond to epidermal growth factor receptor (EGFR) under near UV irradiation. Twelve cysteine mutations were created of an EGFR affibody and conjugated with maleimide-benzophenone. Of these only one exhibited photoconjugation to EGFR, as demonstrated by SDS-PAGE and Western blot. Next this modified affibody was shown to not only bind EGFR expressing cells but also show enhanced retention in a 3D tumor spheroid model, with minimal loss up to 24 h as compared to either unmodified EGFR-binding affibodies or nonbinding, photo-cross-linkable affibodies. Finally, in order to show utility of photo-cross-linking at clinically relevant wavelengths, upconverting nanoparticles (UCNPs) were synthesized that could convert 980 nm light to UV and blue light. In the presence of UCNPs, both direct photoconjugation to EGFR and enhanced retention in tumor spheroids could be obtained using near-infrared illumination. Thus, the photoactive affibodies developed here may be utilized as a platform technology for engineering new therapy conjugates that can penetrate deep into tumor tissue and be retained long enough for effective tumor therapy.

New Generation of Clickable Nucleic Acids: Synthesis and Active Hybridization with DNA.

Due to the ability to generate oligomers of precise sequence, sequential and stepwise solid-phase synthesis has been the dominant method of producing DNA and other oligonucleotide analogues. The requirement for a solid support, however, and the physical restrictions of limited surface area thereon significantly diminish the efficiency and scalability of these syntheses, thus, negatively affecting the practical applications of synthetic polynucleotides and other similarly created molecules. By employing the robust photoinitiated thiol-ene click reaction, we developed a new generation of clickable nucleic acids (CNAs) with a polythioether backbone containing repeat units of six atoms, matching the spacing of the phosphodiester backbone of natural DNA. A simple, inexpensive, and scalable route was utilized to produce CNA monomers in gram-scale, which indicates the potential to dramatically lower the cost of these DNA mimics and thereby expand the scope of these materials. The efficiency of this approach was demonstrated by the completion of CNA polymerization in 30 seconds, as characterized by size-exclusive chromatography (SEC) and infrared (IR) spectroscopy. CNA/DNA hybridization was demonstrated by gel electrophoresis and used in CdS nanoparticle assembly.

DNA-Assembled Core-Satellite Upconverting-Metal-Organic Framework Nanoparticle Superstructures for Efficient Photodynamic Therapy.

DNA-mediated assembly of core-satellite structures composed of Zr(IV)-based porphyrinic metal-organic framework (MOF) and NaYF4 ,Yb,Er upconverting nanoparticles (UCNPs) for photodynamic therapy (PDT) is reported. MOF NPs generate singlet oxygen (1 O2 ) upon photoirradiation with visible light without the need for additional small molecule, diffusional photosensitizers such as porphyrins. Using DNA as a templating agent, well-defined MOF-UCNP clusters are produced where UCNPs are spatially organized around a centrally located MOF NP. Under NIR irradiation, visible light emitted from the UCNPs is absorbed by the core MOF NP to produce 1 O2 at significantly greater amounts than what can be produced from simply mixing UCNPs and MOF NPs. The MOF-UCNP core-satellite superstructures also induce strong cell cytotoxicity against cancer cells, which are further enhanced by attaching epidermal growth factor receptor targeting affibodies to the PDT clusters, highlighting their promise as theranostic photodynamic agents.

Core-shell palladium nanoparticle@metal-organic frameworks as multifunctional catalysts for cascade reactions.

Uniform core-shell Pd@IRMOF-3 nanostructures, where single Pd nanoparticle core is surrounded by amino-functionalized IRMOF-3 shell, are prepared by a facile mixed solvothermal method. When used as multifunctional catalysts, the Pd@IRMOF-3 nanocomposites exhibit high activity, enhanced selectivity, and excellent stability in the cascade reaction. Both experimental evidence and theoretical calculations reveal that the high catalytic performance of Pd@IRMOF-3 nanocomposites originates from their unique core-shell structures.

Crucial role of anions on arrangement of Cu2S nanocrystal superstructures.

Both of the arrays of Cu2S nanowires and the superlattices of Cu2S nanoparticles are obtained by the solventless thermolysis of copper thiolate in the presence of laurate. For the first time, the types of anions in the reaction system, which are generally neglected in previous studies, are found to determine the structure of the final assembly products. Furthermore, experimental results shows in the presence of Cl⁻ ions, Cl⁻ ions participate in the self-assembly process and promote the formation of Cu2S nanowire arrays. Finally, the content of Cl⁻ ions is gradually decreased with assembly reaction proceeding. Therefore, duiring the process, Cl⁻ ions play a role of 'catassembly' in the formation of Cu2S nanocrystal superstructures.

Amperometry for real-time and on-site monitoring of phenol and H2O2 during the treatments.

In conventional wastewater treatment processes, a predetermined quantity of chemicals is introduced at the onset, without ongoing monitoring of the treatment progress. Thus, it is difficult to perform timely intervention in the treatment process. Herein, we develop an amperometry-guided wastewater treatment strategy based on a green oxidation process with H2O2 and an iron-tetraamidomacrocyclic ligand (Fe-TAML) catalyst. During the process, users can monitor both phenol and H2O2 concentrations in real time and then intervene by adding more H2O2 to accelerate the reaction. As a proof of concept, a wastewater sample containing 9.3 ppm of phenol is treated by using the amperometry-guided strategy with 1 dosage of Fe-TAML (0.45 ppm) and 3 dosages of H2O2 (1.86 ppm). After the treatment, phenol concentration in the wastewater decreases to 0 ppm after 21 min. In contrast, with only 1 dosage of Fe-TAML (0.45 ppm) and 1 dosage of H2O2 (1.86 ppm), the reaction slows down after 5 min and stops prematurely. After that, the reaction kinetics of ppb-level phenol are investigated, in which the phenol rate and the rate constant are estimated. Compared to conventional detections, the designed amperometry shows faster response, lower limit of detection (LOD, phenol: 11 ppb, H2O2: 80 ppb) and consumable cost, easier operation, and no pollution generated. This example demonstrates the importance of early intervention during wastewater treatment with the help of real-time information.

Bismuth-Doped Carbon Dots Decorated Escherichia coli for Enhanced Hydrogen Production.

Photosynthetic inorganic biohybrid systems (PBSs) combining an inorganic photosensitizer with intact living cells provide an innovative view for solar hydrogen production. However, typical whole-cell biohybrid systems often suffer from sluggish electron transfer kinetics during transmembrane diffusion, which severely limits the efficiency of solar hydrogen production. Here, a unique biohybrid system with a quantum yield of 8.42% was constructed by feeding bismuth-doped carbon dots (Bi@CDS) to Escherichia coli (E. coli). In this biohybrid system, Bi@CDS can enter the cells and transfer the electrons upon light irradiation, greatly reducing the energy loss and shortening the distance of electron transfer. More importantly, the photocatalytic hydrogen production of the E. coli-Bi@CDs biohybrid system reached up to 0.95 mmol within 3 h under light irradiation (420-780 nm, 2000 W m-2), which is 1.36 and 2.38 times higher than that in the E. coli-CDs biohybrid system and the E. coli system, respectively. In addition, the mechanism of enhanced hydrogen production was further explored. It was found that the accelerated decomposition of glucose, the accelerated production of pyruvate, the inhibition of lactic acid, and the increase of formic acid were the reasons for the increase of hydrogen production. This work provides a novel strategy for improving the hydrogen production in photosynthetic inorganic biohybrid systems.

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.

Bifunctional defect mediated direct Z-scheme g-C3N4-x/Bi2O3-y heterostructures with enhanced piezo-photocatalytic properties for efficient tooth whitening and biofilm eradication.

Biofilm-associated dental diseases and tooth discoloration have recently become the major barriers to achieve healthy teeth. However, there are few effective strategies to address these issues. Herein, the piezo-photocatalytic process is first proposed to be applied for biofilm eradication and tooth whitening with well-designed direct Z scheme g-C3N4-x/Bi2O3-y heterostructures. DFT calculation and XPS results verify the formation of direct Z scheme g-C3N4/Bi2O3 heterostructures theoretically and experimentally. Using the direct Z scheme g-C3N4-x/Bi2O3-y heterostructure, excellent piezo-photocatalytic effects for tooth whitening and biofilm removal are achieved. For piezo-photocatalytic degradation of the typical food colorant of indigo carmine the degradation rate constant is about quadruple that of piezocatalytic and 2.6 times of photocatalytic treatment. Tooth whitening experiments indicate that g-C3N4-x/Bi2O3-y could whiten the stained teeth through the synergistic piezo-photocatalysis. In addition, excellent antibacterial performances can be obtained on the g-C3N4-x/Bi2O3-y heterostructure through piezo-photocatalytic treatment. Not only the planktonic S. mutans but also those bacteria embedded in biofilms can be effectively killed. The analyses of the piezo-photocatalytic mechanism indicates that the enhanced piezo-photocatalytic performance of the g-C3N4-x/Bi2O3-y heterostructure could be attributed to the much higher separation efficiency of photoexcited charge carriers, increased production amounts of ROS and superior adsorption ability for bacteria than those with bare semiconductors of g-C3N4-x and Bi2O3-y and those treated only with ultrasonic vibration or irradiation. Biosafety results show that the g-C3N4-x/Bi2O3-y heterostructure is biologically safe and piezo-photocatalytic treatment has no harm the tooth structure, demonstrating the great potential of piezo-photocatalytic effect based new tooth whitening and antibacterial technology in future dental care fields.

MOF-derived bimetallic nanozyme to catalyze ROS scavenging for protection of myocardial injury.

Rationale: Myocardial injury triggers intense oxidative stress, inflammatory response, and cytokine release, which are essential for myocardial repair and remodeling. Excess reactive oxygen species (ROS) scavenging and inflammation elimination have long been considered to reverse myocardial injuries. However, the efficacy of traditional treatments (antioxidant, anti-inflammatory drugs and natural enzymes) is still poor due to their intrinsic defects such as unfavorable pharmacokinetics and bioavailability, low biological stability, and potential side effects. Nanozyme represents a candidate to effectively modulate redox homeostasis for the treatment of ROS related inflammation diseases. Methods: We develop an integrated bimetallic nanozyme derived from metal-organic framework (MOF) to eliminate ROS and alleviate inflammation. The bimetallic nanozyme (Cu-TCPP-Mn) is synthesized by embedding manganese and copper into the porphyrin followed by sonication, which could mimic the cascade activities of superoxide dismutase (SOD) and catalase (CAT) to transform oxygen radicals to hydrogen peroxide, followed by the catalysis of hydrogen peroxide into oxygen and water. Enzyme kinetic analysis and oxygen-production velocities analysis were performed to evaluate the enzymatic activities of Cu-TCPP-Mn. We also established myocardial infarction (MI) and myocardial ischemia-reperfusion (I/R) injury animal models to verify the ROS scavenging and anti-inflammation effect of Cu-TCPP-Mn. Results: As demonstrated by kinetic analysis and oxygen-production velocities analysis, Cu-TCPP-Mn nanozyme possesses good performance in both SOD- and CAT-like activities to achieve synergistic ROS scavenging effect and provide protection for myocardial injury. In both MI and I/R injury animal models, this bimetallic nanozyme represents a promising and reliable technology to protect the heart tissue from oxidative stress and inflammation-induced injury, and enables the myocardial function to recover from otherwise severe damage. Conclusions: This research provides a facile and applicable method to develop a bimetallic MOF nanozyme, which represents a promising alternative to the treatment of myocardial injuries.

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.