Mn-phenolic networks as synergistic carrier for STING agonists in tumor immunotherapy.

The cGAS-STING pathway holds tremendous potential as a regulator of immune responses, offering a means to reshape the tumor microenvironment and enhance tumor immunotherapy. Despite the emergence of STING agonists, their clinical viability is hampered by stability and delivery challenges, as well as variations in STING expression within tumors. In this study, we present Mn-phenolic networks as a novel carrier for ADU-S100, a hydrophilic STING agonist, aimed at bolstering immunotherapy. These nanoparticles, termed TMA NMs, are synthesized through the coordination of tannic acid and manganese ions, with surface modification involving bovine serum albumin to enhance their colloidal stability. TMA NMs exhibit pH/GSH-responsive disintegration properties, enabling precise drug release. This effectively addresses drug stability issues and facilitates efficient intracellular drug delivery. Importantly, TMA NMs synergistically enhance the effects of ADU-S100 through the concurrent release of Mn2+, which serves as a sensitizer of the STING pathway, resulting in significant STING pathway activation. Upon systemic administration, these nanoparticles efficiently accumulate within tumors. The activation of STING pathways not only induces immunogenic cell death (ICD) in tumor cells but also orchestrates systemic remodeling of the immunosuppressive microenvironment. This includes the promotion of cytokine release, dendritic cell maturation, and T cell infiltration, leading to pronounced suppression of tumor growth. Combining with the excellent biocompatibility and biodegradability, this Mn-based nanocarrier represents a promising strategy for enhancing tumor immunotherapy through the cGAS-STING pathway.

Effect of ion pair strategy on transdermal delivery of guanfacine: Which factor dominates drug permeation?

Ion pair is an effective chemical approach to promoting drug transdermal permeation, and the traditional interpretation for its enhanced permeation effect is mainly attributed to counterions altering the physicochemical properties of the drug (lipophilicity, melting point, etc.). In this work, guanfacine (GFC), a non-stimulant for anti-attention deficit and hyperactivity disorder (ADHD), was used as a model drug, and several organic or inorganic acids were designed thereby successfully constructing ion pairs. The transdermal permeation ability of ion pairs through isolated porcine skin was observed and ranked as follows: guanfacine caprylate (GFC-CA) > GFC > guanfacine laurate (GFC-LA) > guanfacine fumarate (GFC-FA) > guanfacine hydrochloride (GFC-HA) > guanfacine palmitate (GFC-PA). The effect of key physicochemical properties (octanol-water partition coefficient, molecular volume, melting point) on the transdermal permeation rate of the model drug was analyzed in detail. In addition, GFC-CA was observed to alter the lipid structure of the skin, suggesting the traditional explanation of the action of ion pair may be inadequate and underrated, and ion pair may also enhance permeation by disrupting skin structure. The intriguing phenomenon is expected to provide a novel approach to achieving precise transdermal drug delivery.

Converting bacteria into autologous tumor vaccine via surface biomineralization of calcium carbonate for enhanced immunotherapy.

Autologous cancer vaccine that stimulates tumor-specific immune responses for personalized immunotherapy holds great potential for tumor therapy. However, its efficacy is still suboptimal due to the immunosuppressive tumor microenvironment (ITM). Here, we report a new type of bacteria-based autologous cancer vaccine by employing calcium carbonate (CaCO3) biomineralized Salmonella (Sal) as an in-situ cancer vaccine producer and systematical ITM regulator. CaCO3 can be facilely coated on the Sal surface with calcium ionophore A23187 co-loading, and such biomineralization did not affect the bioactivities of the bacteria. Upon intratumoral accumulation, the CaCO3 shell was decomposed at an acidic microenvironment to attenuate tumor acidity, accompanied by the release of Sal and Ca2+/A23187. Specifically, Sal served as a cancer vaccine producer by inducing cancer cells' immunogenic cell death (ICD) and promoting the gap junction formation between tumor cells and dendritic cells (DCs) to promote antigen presentation. Ca2+, on the other hand, was internalized into various types of immune cells with the aid of A23187 and synergized with Sal to systematically regulate the immune system, including DCs maturation, macrophages polarization, and T cells activation. As a result, such bio-vaccine achieved remarkable efficacy against both primary and metastatic tumors by eliciting potent anti-tumor immunity with full biocompatibility. This work demonstrated the potential of bioengineered bacteria as bio-active vaccines for enhanced tumor immunotherapy.

Bacterial Drug Delivery Systems for Cancer Therapy: "Why" and "How".

Cancer is one of the major diseases that endanger human health. However, the use of anticancer drugs is accompanied by a series of side effects. Suitable drug delivery systems can reduce the toxic side effects of drugs and enhance the bioavailability of drugs, among which targeted drug delivery systems are the main development direction of anticancer drug delivery systems. Bacteria is a novel drug delivery system that has shown great potential in cancer therapy because of its tumor-targeting, oncolytic, and immunomodulatory properties. In this review, we systematically describe the reasons why bacteria are suitable carriers of anticancer drugs and the mechanisms by which these advantages arise. Secondly, we outline strategies on how to load drugs onto bacterial carriers. These drug-loading strategies include surface modification and internal modification of bacteria. We focus on the drug-loading strategy because appropriate strategies play a key role in ensuring the stability of the delivery system and improving drug efficacy. Lastly, we also describe the current state of bacterial clinical trials and discuss current challenges. This review summarizes the advantages and various drug-loading strategies of bacteria for cancer therapy and will contribute to the development of bacterial drug delivery systems.

Design and evaluation of gastro-swelling/gastro-floating sustained-release tablets of brivaracetam for epilepsy therapy.

To prolong the absorption of the drug and achieve the effect of gastric retention, new brivaracetam tablets together with the characteristics of rapid swelling and sustained floating have been developed here. The tablets were optimized and prepared by direct compression techniques using Kollidon® SR and cross-linked polyvinylpyrrolidone (PVPP) XL as the matrix and disintegrant respectively, and carbomer 71G NF and polyethylene oxide (PEO) N60K as the gel materials to achieve sustained release effect. The characteristics of static expansion, floating time, drug release and dynamic swelling performance in vitro of the tablets were evaluated. The optimized formulations (F5 and F10) exhibited satisfactory swelling and floating properties, mechanical strength, and in vitro sustained-release characteristic with diffusion and matrix erosion mechanisms. X-ray images of beagle dogs showed that the tablet F5 could be retained in the stomach for more than 6 h. Furthermore, the pharmacokinetic studies in volunteers exhibited that the bioavailability of F5 and F10 was 95.70% (90% CI, 83.80%-109.28%) and 103.39% (90% CI, 87.61%-122.01%), respectively, relative to commercial tablets, with Tmax prolonged, demonstrating an excellent sustained-release effect. Therefore, the present system can reduce dosing frequency and improve patient compliance, which is expected to be a promising treatment option for epilepsy patients.

A General and Efficient Strategy for Gene Delivery Based on Tea Polyphenols Intercalation and Self-Polymerization.

Gene therapy that employs therapeutic nucleic acids to modulate gene expression has shown great promise for diseases therapy, and its clinical application relies on the development of effective gene vector. Herein a novel gene delivery strategy by just using natural polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) as raw material is reported. EGCG first intercalates into nucleic acids to yield a complex, which then oxidizes and self-polymerizes to form tea polyphenols nanoparticles (TPNs) for effective nucleic acids encapsulation. This is a general method to load any types of nucleic acids with single or double strands and short or long sequences. Such TPNs-based vector achieves comparable gene loading capacity to commonly used cationic materials, but showing lower cytotoxicity. TPNs can effectively penetrate inside cells, escape from endo/lysosomes, and release nucleic acids in response to intracellular glutathione to exert biological functions. To demonstrate the in vivo application, an anti-caspase-3 small interfering ribonucleic acid is loaded into TPNs to treat concanavalin A-induced acute hepatitis, and excellent therapeutic efficacy is obtained in combination with the intrinsic activities of TPNs vector. This work provides a simple, versatile, and cost-effective gene delivery strategy. Given the biocompatibility and intrinsic biofunctions, this TPNs-based gene vector holds great potential to treat various diseases.

Topical Delivery of Ketorolac Tromethamine via Cataplasm for Inflammatory Pain Therapy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used in the treatment of inflammatory pain, such as in osteoarthritis. Ketorolac tromethamine is considered to be an NSAID with strong anti-inflammatory and analgesic potency, however, traditional applications, such as oral administration and injections, often induce high systemic exposure, leading to adverse events such as gastric ulceration and bleeding. To address this key limitation, herein we designed and fabricated a topical delivery system for ketorolac tromethamine via cataplasm, which is based on a three-dimensional mesh structure formed by the cross-linking of dihydroxyaluminum aminoacetate (DAAA) and sodium polyacrylate. The viscoelasticity of the cataplasm was characterized by rheological methods and exhibited a "gel-like" elastic property. The release behavior showed a Higuchi model characteristic with a dose dependence. To enhance the skin permeation, permeation enhancers were added and screened utilizing ex vivo pig skin, in which 1,2-propanediol was found to have the optimal permeation-promoting effect. The cataplasm was further applied to a rat carrageenan-induced inflammatory pain model, which showed comparable anti-inflammatory and analgesic effects with oral administration. Finally, the biosafety of the cataplasm was tested in healthy human volunteers, and reduced side effects were achieved as compared to the tablet formulation, which can be ascribed to less systemic drug exposure and lower blood drug concentrations. Therefore, the constructed cataplasm can reduce the risk of adverse events while maintaining efficacy, thus serving as a better alternative for the treatment of inflammatory pain, including osteoarthritis.

Poly-thymine DNA templated MnO2 biomineralization as a high-affinity anchoring enabling tumor targeting delivery.

Manganese oxide nanomaterials (MONs) are emerging as a type of highly promising nanomaterials for diseases diagnosis, and surface modification is the basis for colloidal stability and targeting delivery of the nanomaterials. Here, we report the in-situ functionalization of MnO2 with DNA through a biomineralization process. Using adsorption-oxidation method, DNA templated Mn2+ precursor to biomineralize into nano-cubic seed, followed by the growth of MnO2 to form cube/nanosheet hybrid nanostructure. Among four types of DNA homopolymers, poly-thymine (poly-T) was found to stably attach on MnO2 surface to resist various biological displacements (phosphate, serum, and complementary DNA). Capitalized on this finding, a di-block DNA was rationally designed, in which the poly-T block stably anchored on MnO2 surface, while the AS1411 aptamer block was not only an active ligand for tumor targeting delivery, but also a carrier for photosensitizer (Ce6) loading. Upon targeting delivery into tumor cells, the MnO2 acted as catalase-mimic nanozyme for oxygenation to sensitize photodynamic therapy, and the released Mn2+ triggered chemodynamic therapy via Fenton-like reaction, achieving synergistic anti-tumor effect with full biocompatibility. This work provides a simple yet robust strategy to functionalize metal oxides nanomaterials for biological applications via DNA-templated biomineralization.

Surface engineering Salmonella with pH-responsive polyserotonin and self-activated DNAzyme for better microbial therapy of tumor.

Bacteria-based microbial immunotherapy shows various unique properties for tumor therapy owing to their active tropism to tumor and multiple anti-tumor mechanisms. However, its clinical benefit is far from satisfactory, which is limited by rapid systemic clearance and neutrophils-mediated immune restriction to compromise the efficacy, as well as non-specific distribution to cause toxicity. To address all these limitations, herein we reported a polyserotonin (PST) coated Salmonella (Sal) with surface adsorption of DNAzyme (Dz)-functionalized MnO2 nanoparticles (DzMN) for tumor therapy. PST could facilely coat on Sal surface via oxidation and self-polymerization of its serotonin monomer, which enabled surface stealth to avoid rapid systemic clearance while maintaining the tumor homing effect. Upon targeting to tumor, the PST was degraded and exfoliated in response to acidic tumor microenvironment, thus liberating Sal to recover its anti-tumor activities. Meanwhile, the DzMN was also delivered into tumor via hitchhiking Sal, which could release Dz and Mn2+ after tumor cells internalization. The Dz was then activated by its cofactor of Mn2+ to cleave target PD-L1 mRNA, thus serving as a self-activated system for gene silencing. Combining Sal and Dz for immune activation and PD-L1 knockdown, respectively, anti-tumor immunotherapy was achieved with enhanced efficacy. Notably, PST coating could significantly decrease infection potential and non-specific colonization of Sal at normal organs, achieving high in vivo biosafety. This work addresses the key limitations of Sal for in vivo application via biomaterials modification, and provides a promising platform for better microbial immunotherapy.

Non-cytotoxic nanoparticles re-educating macrophages achieving both innate and adaptive immune responses for tumor therapy.

Macrophages are important antigen-presenting cells to combat tumor via both innate and adaptive immunity, while they are programmed to M2 phenotype in established tumors and instead promote cancer development and metastasis. Here, we develop a nanomedicine that can re-educate M2 polarized macrophages to restore their anti-tumor activities. The nanomedicine has a core-shell structure to co-load IPI549, a PI3Kγ inhibitor, and CpG, a Toll-like receptor 9 agonist. Specifically, the hydrophobic IPI549 is self-assembled into a pure drug nano-core, while MOF shell layer is coated for CpG encapsulation, achieving extra-high total drugs loading of 44%. Such nanosystem could facilitate intracellular delivery of the payloads but without any cytotoxicity, displaying excellent biocompatibility. After entering macrophages, the released IPI549 and CpG exert a synergistic effect to switch macrophages from M2 to M1 phenotype, which enables anti-tumor activities via directly engulfing tumor cells or excreting tumor killing cytokines. Moreover, tumor antigens released from the dying tumor cells could be effectively presented by the re-educated macrophages owing to the up-regulation of various antigen presenting mediators, resulting in infiltration and activation of cytotoxic T lymphocytes. As a result, the nanosystem triggers a robust anti-tumor immune response in combination with PD-L1 antibody to inhibit tumor growth and metastasis. This work provides a non-cytotoxic nanomedicine to modulate tumor immune microenvironment by reprograming macrophages.

Radicals Scavenging MOFs Enabling Targeting Delivery of siRNA for Rheumatoid Arthritis Therapy.

Macrophages play essential roles in the progression of rheumatoid arthritis (RA), which are polarized into the pro-inflammatory M1 phenotype with significant oxidative stress and cytokines excretion. Herein, an active targeting nanomedicine based on metal-organic frameworks (MOFs) to re-educate the diseased macrophages for RA therapy is reported. The MOFs are prepared via coordination between tannic acid (TA) and Fe3+ , and anti-TNF-α siRNA is loaded via a simple sonication process, achieving high loading capacity comparable to cationic vectors. The MOFs show excellent biocompatibility, and enable rapid endo/lysosome escape of siRNA via the proton-sponge effect for effective cytokines down-regulation. Importantly, such nanomedicine displays intrinsic radicals scavenging capability to eliminate a broad spectrum of reactive oxygen and nitrogen species (RONS), which in turn repolarizes the M1 macrophages into anti-inflammatory M2 phenotypes for enhanced RA therapy in combination with siRNA. The MOFs are further modified with bovine serum albumin (BSA) to allow cascade RA joint and diseased macrophages targeted delivery. As a result, an excellent anti-RA efficacy is achieved in a collagen-induced arthritis mice model. This work provides a robust gene vector with great translational potential, and offers a vivid example of rationally designing MOF structure with multifunctionalities to synergize with its payload for enhanced disease treatment.

Fenton metal nanomedicines for imaging-guided combinatorial chemodynamic therapy against cancer.

Chemodynamic therapy (CDT) is considered as a promising modality for selective cancer therapy, which is realized via Fenton reaction-mediated decomposition of endogenous H2O2 to produce toxic hydroxyl radical (•OH) for tumor ablation. While extensive efforts have been made to develop CDT-based therapeutics, their in vivo efficacy is usually unsatisfactory due to poor catalytic activity limited by tumor microenvironment, such as anti-oxidative systems, insufficient H2O2, and mild acidity. To mitigate these issues, we have witnessed a surge in the development of CDT-based combinatorial nanomedicines with complementary or synergistic mechanisms for enhanced tumor therapy. By virtue of their bio-imaging capabilities, Fenton metal nanomedicines (FMNs) are equipped with intrinsic properties of imaging-guided tumor therapies. In this critical review, we summarize recent progress of this field, focusing on FMNs for imaging-guided combinatorial tumor therapy. First, various Fenton metals with inherent catalytic performances and imaging properties, including Fe, Cu and Mn, were introduced to illustrate their possible applications for tumor theranostics. Then, CDT-based combinatorial systems were reviewed by incorporating many other treatment means, including chemotherapy, photodynamic therapy (PDT), sonodynamic therapy (SDT), photothermal therapy (PTT), starvation therapy and immunotherapy. Next, various imaging approaches based on Fenton metals were presented in detail. Finally, challenges are discussed, and future prospects are speculated in the field to pave way for future developments.

Polyserotonin as a versatile coating with pH-responsive degradation for anti-tumor therapy.

Through self-polymerization of serotonin monomer, polyserotonin (PST) can coat on arbitrary surfaces with pH-responsive degradation, which was employed for nanoparticle coating and controlled drug release, achieving a robust anti-tumor effect when combined with its intrinsic photothermal effect.

Intrinsic Radical Species Scavenging Activities of Tea Polyphenols Nanoparticles Block Pyroptosis in Endotoxin-Induced Sepsis.

Sepsis, a life-threating illness caused by deregulated host immune responses to infections, is characterized by overproduction of multiple reactive oxygen and nitrogen species (RONS) and excessive pyroptosis, leading to high mortality. However, there is still no approved specific molecular therapy to treat sepsis. Here we reported drug-free tea polyphenols nanoparticles (TPNs) with intrinsic broad-spectrum RONS scavenging and pyroptosis-blocking activities to treat endotoxin (LPS)-induced sepsis in mice. The RONS scavenging activities originated from the polyphenols-derived structure, while the pyroptosis blockage was achieved by inhibiting gasdermin D (GSDMD) mediating the pore formation and membrane rupture, showing multifunctionalities for sepsis therapy. Notably, TPNs suppress GSDMD by inhibiting the oligomerization of GSDMD rather than the cleavage of GSDMD, thus displaying high pyroptosis-inhibition efficiency. As a result, TPNs showed an excellent therapeutic efficacy in sepsis mice model, as evidenced by survival rate improvement, hypothermia amelioration, and the organ damage protection. Collectively, TPNs present biocompatible candidates for the treatment of sepsis.

Surface Coating of Pulmonary siRNA Delivery Vectors Enabling Mucus Penetration, Cell Targeting, and Intracellular Radical Scavenging for Enhanced Acute Lung Injury Therapy.

Pulmonary delivery of anti-inflammatory siRNA presents a promising approach for localized therapy of acute lung injury (ALI), while polycationic vectors can be easily trapped by the negatively charged airway mucin glycoproteins and arbitrarily internalized by epithelial cells with nontargetability for immunological clearance. Herein, we report a material, the dopamine (DA)-grafted hyaluronic acid (HA-DA), coating on an anti-TNF-α vector to address these limitations. HA-DA was simply synthesized and facilely coated on poly(ß-amino ester) (BP)-based siRNA vectors via electrostatic attraction. The resulting HA-DA/BP/siRNA displayed significantly enhanced mucus penetration, attributable to the charge screen effect of HA-DA and the bioadhesive nature of the grafting DA. After transmucosal delivery, the nanosystem could target diseased macrophages via CD44-mediated internalization and rapidly escape from endo/lysosomes through the proton sponge effect, resulting in effective TNF-α regulation. Meanwhile, DA modification endowed the coating material with robust antioxidative capability to scavenge a broad spectrum of reactive oxygen/nitrogen species (RONS), which protected the lung tissue from oxidative damage and synergized with anti-TNF-α to inhibit a cytokine storm. As a result, a remarkable amelioration of ALI was achieved in a lipopolysaccharide (LPS)-stimulated mice model. This study provides a multifunctional coating material to facilitate pulmonary drug delivery for the treatment of lung diseases.

A double-blind, randomized, placebo and positive-controlled study in healthy volunteers to evaluate pharmacokinetic and pharmacodynamic properties of multiple oral doses of cetagliptin.

AIMS: This study investigated the pharmacokinetics and pharmacodynamics properties, safety and tolerability of cetagliptin. METHODS: Forty-eight healthy subjects were enrolled in this study. Three cohorts were investigated in sequential order: 50, 100 and 200 mg cetagliptin. Positive control (sitagliptin 100 mg) was designed as open label. Blood samples were collected and analysed for pharmacokinetic and pharmacodynamic properties. Safety and tolerability were assessed throughout the study. RESULTS: Following multiple oral doses, cetagliptin was rapidly absorbed and reached peak plasma concentrations after approximately 1.0-1.5 hours. Plasma cetagliptin concentrations increased at a rate greater than dose. Accumulation of cetagliptin was modest, and steady state was generally achieved at day 5. Doses ≥50 mg of cetagliptin administered once daily will result in sustained dipeptidyl peptidase-4 (DPP-4) inhibition (≥80%). The plasma concentration giving 50% of maximum drug effect of DPP-4 inhibition for cetagliptin (5.29 ng/mL) was lower than that of sitagliptin (7.03 ng/mL). Active glucagon-like-1 peptide (GLP-1) concentrations were significantly increased in the cetagliptin groups by 2.3- to 3.1-fold at day 1 and 3.1- to 3.6-fold at steady state compared with that of placebo, and active GLP-1 concentrations were increased with increasing dose. Compared with sitagliptin, doses ≥100 mg once daily of cetagliptin produced postprandial increases in active GLP-1 level and induced to long-lasting glucose-lowering efficacy. Cetagliptin was well tolerated across all doses studied. CONCLUSION: Cetagliptin demonstrates the great potential for treatment with type 2 diabetes patients based on the inhibition of DPP-4, the increase in GLP-1 and insulin, the decrease in glucose, and might be more effective in DPP-4 inhibition than sitagliptin.

The metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C] cetagliptin in healthy volunteers.

The metabolism and excretion of cetagliptin were investigated in healthy male subjects after a single oral dose of 100mg/50µCi [14C] cetagliptin.The mean concentration-time profile of cetagliptin was similar to that of total radioactivity in plasma after oral administration of [14C] cetagliptin in healthy male subjects. Cetagliptin was rapidly absorbed after oral administration. Unchanged cetagliptin was the most abundant radioactive component in all matrices investigated. Approximately 53.13% of plasma AUC of total radioactivity was accounted for by cetagliptin. Each metabolite plasma AUC was not higher than 2.93% of plasma AUC of total radioactivity. By 336 h after administration, 91.68% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 72.88% and 18.81%, respectively. The primary route of excretion of radioactivity was via the kidneys.Four metabolites were detected at trace levels, and it involved hydroxylated (M436-1 and M436-3), N- sulphate (M500), and N-carbamoyl glucuronic acid conjugates (M640B) of cetagliptin. These metabolites were detected also in plasma, urine, and faeces at low levels, except that metabolite M640B was not detected in faeces. All metabolites were observed with <10% of parent compound systemic exposure after oral administration.

Anti-PD-L1 DNAzyme Loaded Photothermal Mn2+ /Fe3+ Hybrid Metal-Phenolic Networks for Cyclically Amplified Tumor Ferroptosis-Immunotherapy.

Ferroptosis can activate immune response via inducing tumor cells immunogenic cell death (ICD), and antitumor immunity in turn boosts the efficacy of ferroptosis by excreting interferon gamma (IFN-γ), which shows a promising combo for synergistically amplified tumor treatment. However, their combination is strictly limited by the complexity of tumor microenvironment, including poor ferroptosis response and immunosuppressive factors in tumor. Herein, a metal-phenolic networks (MPNs) nanoplatform with all-active components is constructed to favor the ferroptosis-immunotherapy cyclical synergism. The photothermal MPNs are assembled via coordination between tannic acid (TA) and metal-ion complex of Fe3+ /Mn2+ , through which a PD-L1 inhibiting DNAzyme (DZ) is loaded to regulate the immunosuppressive PD-1/PD-L1 pathway. After intracellular delivery, each component of MPNs exerts their respective functions: Fe2+ is in situ generated from Fe3+ by TA reduction to trigger ferroptosis, while DZ is activated by Mn2+ to effectively silence PD-L1. With external laser irradiation, photothermal therapy is initiated to synergize with ferroptosis for enhanced ICD, which induces strong antitumor immunes. Combined with DZ-mediated PD-L1 suppression, a cyclically amplified tumor ferroptosis-immunotherapy is achieved, resulting in obliteration of both primary and distant tumor. This work provides a smart, simple, yet robust nanomedicine-based combination for self-amplified tumor treatment.

Polarity control of DNA adsorption enabling the surface functionalization of CuO nanozymes for targeted tumor therapy.

Nanomaterials with intrinsic catalytic activities (nanozyme) have drawn broad attention for various biomedical applications, with peroxidase-mimic nanozymes particularly attractive for cancer therapy due to their capability to catalyze the conversion of tumor-abundant H2O2 into more toxic hydroxyl radicals (˙OH) for effective tumor ablation. However, the facile surface modification of nanozymes for tumor-targeted delivery while retaining their catalytic activity remains a challenge. Here, we report an approach to functionalize the CuO nanozyme with DNA to enable targeted delivery and selective tumor destruction. We systematically studied the adsorption of DNA on the CuO surface, with special attention paid to the catalytic activity and DNA adsorption stability in the presence of various biological ligands. After gaining a fundamental understanding, a di-block DNA sequence was designed for adsorption on to the CuO surface, which allowed stable adsorption during in vivo circulation, passive accumulation into the tumor tissue, and the specific recognition of tumor cells, resulting in significant nanocatalytic tumor suppression in tumor xenograft mice models with no noticeable cytotoxicity. This work paves a way for the rational design of DNA-modified nanozymes for catalytic tumor therapy, and fundamentally, provides a new insight into the biointerface chemistry of CuO with DNA.