The Convergence of Sonodynamic Therapy and Cuproptosis in the Dual-Responsive Biomimetic CytoNano for Precision Mitochondrial Intervention in Cancer Treatment.

The integration of sonodynamic therapy (SDT) with cuproptosis for targeted cancer treatment epitomizes a significant advancement in oncology. Herein, we present a dual-responsive therapeutic system, "CytoNano", which combines a cationic liposome infused with copper-nitride nanoparticles and oxygen-rich perfluorocarbon (Lip@Cu3N/PFC-O2), all enveloped in a biomimetic coating of neutrophil membrane and acid-responsive carboxymethylcellulose. CytoNano leverages the cellular mimicry of neutrophils and acid-responsive materials, enabling precise targeting of tumors and their acidic microenvironment. This strategic design facilitates the targeted release of Lip@Cu3N/PFC-O2 within the tumor, enhancing cancer cell uptake and mitochondrial localization. Consequently, it amplifies the therapeutic efficacy of both Cu3N-driven SDT and cuproptosis while preserving healthy tissues. Additionally, CytoNano's ultrasound responsiveness enhances intratumoral oxygenation, overcoming physiological barriers and initiating a combined sonodynamic-cuproptotic effect that induces multiple cell death pathways. Thus, we pioneer a biomimetic approach in precise sonodynamic cuproptosis, revolutionizing cancer therapy.

Frequency-encoded eye tracking smart contact lens for human-machine interaction.

Eye tracking techniques enable high-efficient, natural, and effortless human-machine interaction by detecting users' eye movements and decoding their attention and intentions. Here, a miniature, imperceptible, and biocompatible smart contact lens is proposed for in situ eye tracking and wireless eye-machine interaction. Employing the frequency encoding strategy, the chip-free and battery-free lens successes in detecting eye movement and closure. Using a time-sequential eye tracking algorithm, the lens has a great angular accuracy of <0.5°, which is even less than the vision range of central fovea. Multiple eye-machine interaction applications, such as eye-drawing, Gluttonous Snake game, web interaction, pan-tilt-zoom camera control, and robot vehicle control, are demonstrated on the eye movement model and in vivo rabbit. Furthermore, comprehensive biocompatibility tests are implemented, demonstrating low cytotoxicity and low eye irritation. Thus, the contact lens is expected to enrich approaches of eye tracking techniques and promote the development of human-machine interaction technology.

Cellular Trojan Horse initiates bimetallic Fe-Cu MOF-mediated synergistic cuproptosis and ferroptosis against malignancies.

Disruptions in metal balance can trigger a synergistic interplay of cuproptosis and ferroptosis, offering promising solutions to enduring challenges in oncology. Here, we have engineered a Cellular Trojan Horse, named MetaCell, which uses live neutrophils to stably internalize thermosensitive liposomal bimetallic Fe-Cu MOFs (Lip@Fe-Cu-MOFs). MetaCell can instigate cuproptosis and ferroptosis, thereby enhancing treatment efficacy. Mirroring the characteristics of neutrophils, MetaCell can evade the immune system and not only infiltrate tumors but also respond to inflammation by releasing therapeutic components, thereby surmounting traditional treatment barriers. Notably, Lip@Fe-Cu-MOFs demonstrate notable photothermal effects, inciting a targeted release of Fe-Cu-MOFs within cancer cells and amplifying the synergistic action of cuproptosis and ferroptosis. MetaCell has demonstrated promising treatment outcomes in tumor-bearing mice, effectively eliminating solid tumors and forestalling recurrence, leading to extended survival. This research provides great insights into the complex interplay between copper and iron homeostasis in malignancies, potentially paving the way for innovative approaches in cancer treatment.

A living neutrophil Biorobot synergistically blocks multifaceted inflammatory pathways in macrophages to effectively neutralize cytokine storm.

Cytokine storm is a potentially life-threatening immune response typically correlated with lung injury, particularly in people with underlying disease states, such as pneumonia. Therefore, the prompt treatment of cytokine storm is essential for successful recovery from a potentially fatal condition. Herein, a living anti-inflammatory Biorobot (firefighter), composed of neutrophils encapsulating mannose-decorated liposomes of the NF-κB inhibitor TPCA-1 and STING inhibitor H-151 (M-Lip@TH, inflammatory retardant), is developed for alleviating hyperinflammatory cytokine storm through targeting multiple inflammatory pathways in macrophages. Biorobot fully inherits the chemotaxis characteristics of neutrophils, and efficiently delivers and releases therapeutic M-Lip@TH at the inflammatory site. Subsequently, M-Lip@TH selectively targets macrophages and simultaneously blocks the transcription factor NF-κB pathway and STING pathway, thereby preventing the overproduction of cytokines. Animal studies show that Biorobot selectively targets LPS-induced acute lung injury, and not only inhibits the NF-κB pathway to suppress the release of various pro-inflammatory cytokines and chemokines, but also blocks the STING pathway to prevent an overactive immune response, which helps to neutralize cytokine storms. Particularly, Biorobot reduces lung inflammation and injury, improves lung function, and increases the survival rates of pneumonia mice. Therefore, Biorobot represents a rational combination therapy against cytokine storm, and may provide insights into the treatment of diseases involving overactive immune responses.

Porous Microneedles Through Direct Ink Drawing with Nanocomposite Inks for Transdermal Collection of Interstitial Fluid.

Interstitial fluid (ISF) is an attractive alternative to regular blood sampling for health checks and disease diagnosis. Porous microneedles (MNs) are well suited for collecting ISF in a minimally invasive manner. However, traditional methods of molding MNs from microfabricated templates involve prohibitive fabrication costs and fixed designs. To overcome these limitations, this study presents a facile and economical additive manufacturing approach to create porous MNs. Compared to traditional layerwise build sequences, direct ink drawing with nanocomposite inks can define sharp MNs with tailored shapes and achieve vastly improved fabrication efficiency. The key to this fabrication strategy is the yield-stress fluid ink that is easily formulated by dispersing silica nanoparticles into the cellulose acetate polymer solution. As-printed MNs are solidified into interconnected porous microstructure inside a coagulation bath of deionized water. The resulting MNs exhibit high mechanical strength and high porosity. This approach also allows porous MNs to be easily integrated on various substrates. In particular, MNs on filter paper substrates are highly flexible to rapidly collect ISF on non-flat skin sites. The extracted ISF is used for quantitative analysis of biomarkers, including glucose, = calcium ions, and calcium ions. Overall, the developments allow facile fabrication of porous MNs for transdermal diagnosis and therapy.

Bioengineered Neutrophils for Smart Response in Brain Infection Management.

Brain infections, frequently accompanied by significant inflammation, necessitate comprehensive therapeutic approaches targeting both infections and associated inflammation. A major impediment to such combined treatment is the blood-brain barrier (BBB), which significantly restricts therapeutic agents from achieving effective concentrations within the central nervous system. Here, a neutrophil-centric dual-responsive delivery system, coined "CellUs," is pioneered. This system is characterized by live neutrophils enveloping liposomes of dexamethasone, ceftriaxone, and oxygen-saturated perfluorocarbon (Lipo@D/C/P). CellUs is meticulously engineered to co-deliver antibiotics, anti-inflammatory agents, and oxygen, embodying a comprehensive strategy against brain infections. CellUs leverages the intrinsic abilities of neutrophils to navigate through BBB, accurately target infection sites, and synchronize the release of Lipo@D/C/P with local inflammatory signals. Notably, the incorporation of ultrasound-responsive perfluorocarbon within Lipo@D/C/P ensures the on-demand release of therapeutic agents at the afflicted regions. CellUs shows considerable promise in treating Staphylococcus aureus infections in mice with meningitis, particularly when combined with ultrasound treatments. It effectively penetrates BBB, significantly eliminates bacteria, reduces inflammation, and delivers oxygen to the affected brain tissue, resulting in a substantial improvement in survival rates. Consequently, CellUs harnesses the natural chemotactic properties of neutrophils and offers an innovative pathway to improve treatment effectiveness while minimizing adverse effects.

An Integrative Bioorthogonal Nanoengineering Strategy for Dynamically Constructing Heterogenous Tumor Spheroids.

Although tumor models have revolutionized perspectives on cancer aetiology and treatment, current cell culture methods remain challenges in constructing organotypic tumor with in vivo-like complexity, especially native characteristics, leading to unpredictable results for in vivo responses. Herein, the bioorthogonal nanoengineering strategy (BONE) for building photothermal dynamic tumor spheroids is developed. In this process, biosynthetic machinery incorporated bioorthogonal azide reporters into cell surface glycoconjugates, followed by reacting with multivalent click ligand (ClickRod) that is composed of hyaluronic acid-functionalized gold nanorod carrying dibenzocyclooctyne moieties, resulting in rapid construction of tumor spheroids. BONE can effectively assemble different cancer cells and immune cells together to construct heterogenous tumor spheroids is identified. Particularly, ClickRod exhibited favorable photothermal activity, which precisely promoted cell activity and shaped physiological microenvironment, leading to formation of dynamic features of original tumor, such as heterogeneous cell population and pluripotency, different maturation levels, and physiological gradients. Importantly, BONE not only offered a promising platform for investigating tumorigenesis and therapeutic response, but also improved establishment of subcutaneous xenograft model under mild photo-stimulation, thereby significantly advancing cancer research. Therefore, the first bioorthogonal nanoengineering strategy for developing dynamic tumor models, which have the potential for bridging gaps between in vitro and in vivo research is presented.

Multifunctional Microneedle Patches via Direct Ink Drawing of Nanocomposite Inks for Personalized Transdermal Drug Delivery.

Additive manufacturing, commonly known as 3D printing, allows decentralized drug fabrication of orally administered tablets. Microneedles are comparatively favorable for self-administered transdermal drug delivery with improved absorption and bioavailability. Due to the cross-scale geometric characteristics, 3D-printed microneedles face a significant trade-off between the feature resolution and production speed in conventional layer-wise deposition sequences. In this study, we introduce an economical and scalable direct ink drawing strategy to create drug-loaded microneedles. A freestanding microneedle is efficiently generated upon each pneumatic extrusion and controlled drawing process. Sharp tips of ∼5 µm are formed with submillimeter nozzles, representing 2 orders of magnitude improved resolution. As the key enabler of this fabrication strategy, the yield-stress fluid inks are formulated by simply filling silica nanoparticles into regular polymer solutions. The approach is compatible with various microneedles based on dissolvable, biodegradable, and nondegradable polymers. Various matrices are readily adopted to adjust the release behaviors of the drug-loaded microneedles. Successful fabrication of multifunctional patches with heterogeneously integrated microneedles allows the treatment of melanoma via synergistic photothermal therapy and combination chemotherapy. The personalized patches are designed for cancer severity to achieve high therapeutic efficacy with minimal side effects. The direct ink drawing reported here provides a facile and low-cost fabrication strategy for multifunctional microneedle patches for self-administering transdermal drug delivery.

Scaffold-Free Multicellular 3D Tissue Constructs Utilizing Bio-orthogonal Click Strategy.

Multicellular 3D tissue constructs (MTCs) are important in biomedical research due to their capacity to accurately mimic the structure and variation found in real tissues. This study presents a novel bio-orthogonal engineering strategy (BIEN), a transformative scaffold-free approach, to create advanced MTCs. BIEN harnesses the cellular biosynthetic machinery to incorporate bio-orthogonal azide reporters into cell surface glycoconjugates, followed by a click reaction with multiarm PEG, resulting in rapid assembly of MTCs. The implementation of this cutting-edge strategy culminates in the formation of uniform, heterogeneous spheroids, characterized by a high degree of intercellular junction and pluripotency. Remarkably, MTCs simulate tumor features, ensure cell heterogeneity, and significantly improve the subcutaneous xenograft model after transplantation, thereby bolstering both in vitro and in vivo research models. In conclusion, the utilization of the bio-orthogonal engineering strategy as a scaffold-free method to generate superior MTCs holds promising potential for driving advancements in cancer research.

Bioengineered Neutrophil Extinguisher Targets Cascade Immune Pathways of Macrophages for Alleviating Cytokine Storm in Pneumonia.

Cytokine storm is a common complication of COVID-19 pneumonia and has been proven to contribute to high mortality rates. However, current treatment approaches exhibit limited potential to balance immune response and overproduction of inflammatory cytokines, leading to poor therapeutic outcomes. Herein, a smart bioengineered neutrophil, Extinguisher, composed of live neutrophils encapsulating the liposome formulation of NF-κB suppressor MLN4924 and STING inhibitor H-151 (Lip@MH), is developed for alleviating the hyperinflammatory cytokine storm. Extinguisher inherits motility and chemotaxis characteristics of neutrophils, allowing for the specific delivery and sustained release of Lip@MH within inflamed tissues. Subsequently, Lip@MH effectively transports anti-inflammatory agents into macrophages and synergistically inhibits inflammatory pathways of NF-κB and STING, leading to decreased production of cytokines. In vivo studies demonstrate that Extinguisher not only selectively accumulates at the site of pneumonia caused by Pseudomonas aeruginosa-induced acute lung injury but inhibits the production of inflammatory factors through regulating NF-κB/STING signaling pathways, thereby effectively calming cytokine storm. Importantly, Extinguisher significantly improves therapeutic benefits and survival in mice with acute pneumonia. Therefore, Extinguisher represents an appropriate combination of cell therapy and immunoregulation for cytokine storm intervention and may bring insights into the treatment of COVID-19 pneumonia.

A Responsive Nanorobot Modulates Intracellular Zinc Homeostasis to Amplify Mitochondria-Targeted Phototherapy.

Zinc has been proven to interweave with many critical cell death pathways, and not only exhibits potent anticancer activity solely, but sensitizes cancer cells to anticancer treatment, making zinc supplementation ideal for boosting odds against malignancy. Herein, a smart nanorobot (termed as Zinger) is developed, composed of iRGD-functionalized liposome encapsulating black phosphorus nanosheet (BPNs) doped zeolite imidazole framework-8 (BPN@ZIF-8), for advancing zinc-promoted photodynamic therapy (PDT). Zinger exhibits photo-triggered sequential mitochondria-targeting ability, and can induce zinc overload-mediated mitochondrial stress, which consequently sensitized tumor to PDT through synergistically modulating reactive oxygen species (ROS) production and p53 pathway. It is identified that Zinger selectively triggered intracellular zinc overload and photodynamic effect in cancer cells, which together enhanced PDT treatment outcomes. Importantly, Zinger shows high efficacy in overcoming various treatment barriers, allowing for effectively killing cancer cells in the complex circumstances. Particularly, Zinger exhibits good tumor accumulation, penetration, and even cell uptake, and can respond to light stimulation to eliminate tumors while avoiding normal tissues, thereby prolonging survival of tumor-bearing mice. Therefore, the study provides a novel insight in the development of novel zinc-associated therapy for advancing cancer treatment approaches.

A photoactive self-healing carboxymethyl chitosan-based hydrogel for accelerated infected wound healing through simultaneously modulating multiple critical tissue repair factors.

Infected wounds cause severe medical complications and even chronic mortality, leading to persistent health burdens. Therefore, the enhancement of wound healing has been a major goal of medical researchers. Herein, a photoactive self-healing hydrogel (termed as Macropatch), composed of carboxymethyl chitosan (CMCS), tannic acid (TA) and graphitic carbon nitride g-C3N4 (GCN), was developed to promote wound healing through simultaneously modulating pathological related factors. We identified that dynamic hydrogen bond, hydrophobic interaction and crosslinking between hydrogel backbones endowed Macropatch with good self-healing capability and mechanical property, allowing for protecting the wound from further injury. In addition, Macropatch exhibited superior tissue adhesiveness and cell affinity due to numerous catechol groups of TA chains, and enabled tight wound adhesion to seal organ bleeding. Specifically, GCN endowed Macropatch with improving mechanical strength, self-healing ability and especially visible light-induced antibacterial activity, leading to a fast recovery of bacteria-infected wounds. More remarkably, benefiting from inherent and photodynamic antibacterial properties, Macropatch could prevent bacterial infections under visible light irradiation, and consequently increase the collagen synthesis and re-epithelization, accelerating bacteria-infected wound healing process. Overall, photoactive Macropatch is a safe wound dressing with the potential of overcoming challenges in infectious wound healing, and might be applied in clinical condition.

An Intelligent Cell-Derived Nanorobot Bridges Synergistic Crosstalk Between Sonodynamic Therapy and Cuproptosis to Promote Cancer Treatment.

Recent progress in cuproptosis sheds light on the development of treatment approaches for advancing sonodynamic therapy (SDT) due to its unique cell death mechanism. Herein, we elaborately developed an intelligent cell-derived nanorobot (SonoCu), composed of macrophage-membrane-camouflaged nanocarrier encapsulating copper-doped zeolitic imidazolate framework-8 (ZIF-8), perfluorocarbon, and sonosensitizer Ce6, for synergistically triggering cuproptosis-augmented SDT. SonoCu not only improved tumor accumulation and cancer-cell uptake through cell-membrane camouflaging but responded to ultrasound stimuli to enhance intratumor blood flow and oxygen supply, which consequently overcame treatment barriers and activated sonodynamic cuproptosis. Importantly, the SDT effectiveness could be further amplified by cuproptosis through multiple mechanisms, including reactive oxygen species accumulation, proteotoxic stress, and metabolic regulation, which synergistically sensitized cancer cell death. Particularly, SonoCu exhibited ultrasound-responsive cytotoxicity against cancer cells but not healthy cells, endowing it with good biosafety. Therefore, we present the first anticancer combination of SDT and cuproptosis, which may inspire studies pursuing a rational multimodal treatment strategy.

Light-Activated Chemically Reactive Fibrous Patch Revolutionizes Wound Repair Through the Prevention of Postoperative Adhesion.

A light-activated chemically reactive fibrous patch (ChemPatch) with tissue adhesion and wound healing activity was developed for preventing postoperative peritoneal adhesion. ChemPatch was constructed by an integrative electrospinning fabrication strategy, generating multifunctional PCL-NHS fibers encapsulating antioxidant curcumin and MnO2 nanoparticles. ChemPatch exhibited excellent photothermal conversion, which not only reformed the physical state to match the tissue but also improved conjugation between ChemPatch and tissues, allowing for strong attachment. Importantly, ChemPatch possessed good antioxidant and radical scavenging activity, which protected cells in an oxidative microenvironment and improved tissue regeneration. Particularly, ChemPatch acted as a multifunctional barrier and could not only promote reepithelialization and revascularization in wound defect model but simultaneously ameliorate inflammation and prevent postoperative peritoneal adhesion in a mouse cecal defect model. Thus, ChemPatch represents a dual-active bioadhesive barrier for reducing the incidence and severity of peritoneal adhesions.

Stretchable and Skin-Attachable Electronic Device for Remotely Controlled Wearable Cancer Therapy.

Surgery represents a primary clinical treatment of solid tumors. The high risk of local relapse typically requires frequent hospital visits for postoperative adjuvant therapy. Here, device designs and system integration of a stretchable electronic device for wearable cancer treatment are presented. The soft electronic patch harnesses compliant materials to achieve conformal and stable attachment to the surgical wound. A composite nanotextile dressing is laminated to the electronic patch to allow the on-demand release of anticancer drugs under electro-thermal actuation. An additional flexible circuit and a compact battery complete an untethered wearable system to execute remote therapeutic commands from a smartphone. The successful implementation of combined chemothermotherapy to inhibit tumor recurrence demonstrates the promising potential of stretchable electronics for advanced wearable therapies without interfering with daily activities.

Smart Metabolism Nanovalve Reprograms Cancer Energy Homeostasis for Maximizing Photometabolism Therapy.

Better understanding of important roles of metabolic reprogramming in therapeutic resistance provides insights into advancing cancer treatment. Herein, we present a photoactive metabolic reprogramming strategy (termed as photometabolism therapy, PMT), in which photoregulation of mitochondria leads to cancer cell metabolic crisis, and consequently overcomes therapeutic resistance while improving treatment efficacy. In specific, a stimuli-responsive metabolism NanoValve is developed for improving cascade cancer therapy through blocking mitochondrial energy supply. NanoValve is composed of an onion-like architecture with a gold nanorod core, a mesoporous silica shell encapsulating photosensitizer chlorin e6 and oxygen-saturated perfluorocarbon, and cationic liposomal coating with MMP2-cleavable polyethylene glycol corona, which together initiate mitochondria-specific PMT. NanoValve selectively responds to tumor-overexpressed MMP2 and achieves size decrease and charge reversal, which consequently enhances tumor penetration, cancer cell uptake, endosome escape, and most critically, mitochondrial accumulation. Importantly, NanoValve-mediated phototherapy can strongly destruct mitochondrial energy metabolism, thereby minimizing therapy resistance. Particularly, perfluorocarbon supplies oxygen to further overcome the tumor hypoxia-associated therapeutic barrier and maximizes synergistic anticancer effects. In vivo studies show that NanoValve can effectively eliminate tumors without side effects, thereby dramatically prolonging the survival of tumor-bearing mice. Thus, NanoValve provides a modular PMT approach and has the potential of advancing the treatment of malignancy.

Orthogonal Chemical Reporter Strategy Enables Sensitive and Specific SERS Detection of Hydrazine Derivatives.

Hydrazine and its derivatives are well-known environmental hazards and biological carcinogens; therefore, there is a great need for a powerful workflow solution for protecting the public from unexpected exposure to toxic contaminants. Recently, functional surface-enhanced Raman scattering (SERS) exhibits enormous benefits in sensing trace biochemical substances due to its fingerprint-like identification of individual molecules, making it an ideal method for detecting and quantifying hydrazine. Herein, for the first time, we integrated the orthogonal chemical reporter strategy with SERS to build an intelligent hydrazine detection platform (orthogonal chemical SERS, ocSERS), in which 4-mercaptobenzaldehyde was incorporated on a nanoimprinted gold nanopillar array, which acted as an orthogonal coupling partner of hydrazine to form Raman active benzaldehyde hydrazone, allowing for sensitively detecting hydrazine with a detection limit of 10-13 M in complex circumstances. Particularly, ocSERS could effectively identify the carcinogen N-nitrosodimethylamine (NDMA) after its reduction to dimethylhydrazine (UDMH), enabling ultrasensitive detection of UDMH (10-13 M). Importantly, ocSERS could not only monitor elevated levels of NDMA in ranitidine due to improper storage but also quantify NDMA in urine and blood after oral administration of NDMA-containing drugs, thereby preventing NDMA overexposure. Therefore, ocSERS represents the first click SERS sensor and may open up a new analytical field.

A Smart "Energy NanoLock" Selectively Blocks Oral Cancer Energy Metabolism through Synergistic Inhibition of Exogenous Nutrient Supply and Endogenous Energy Production.

The major challenge in oral cancer is the lack of state-of-the-art treatment modality that effectively cures cancer while preserving oral functions. Recent insights into tumor metabolic dependency provide a therapeutic opportunity for exploring optimal treatment approaches. Herein, a smart responsive "Energy NanoLock" is developed to improve cancer metabolic intervention by simultaneously inhibiting nutrient supply and energy production. NanoLock is a pomegranate-like nanocomplex of cyclicRGD-modified carboxymethyl chitosan (CyclicRC, pI = 6.7) encapsulating indocyanine green and apoptotic peptides functionalized gold nanoparticles (IK-AuNPs), which together form a dual pH- and photoresponsive therapeutic platform. NanoLock exhibits good stability under physiological conditions, but releases small-size CyclicRC and IK-AuNPs in response to the tumor acidic microenvironment, leading to deep tumor penetration. CyclicRC targets integrins to inhibit tumor angiogenesis, and consequently blocks tumor nutrient supply. Meanwhile, IK-AuNPs specifically induce apoptotic peptides and photothermally mediated mitochondrial collapse, and consequently inhibits endogenous energy production, thereby facilitating cell death. Importantly, in both xenograft and orthotopic oral cancer models, NanoLock selectively eliminates tumors with little cross-reactivity with normal tissues, especially oral functions, resulting in prolonged survival of mice. Therefore, NanoLock provides a novel metabolic therapy to exploit synergistic inhibition of exogenous nutrient supply and endogenous energy production, which potentially advances oral cancer treatment.

Integrative Strategy for Investigating the Interactions between STING and Small-Molecule Ligands.

Although small-molecule agonists of stimulator of interferon genes (STING) show significance in activating the immune system, the dynamic process involved in ligands activating STING remains unclear. Herein, we developed a biochemical strategy, integrating computer simulation and a biochemical engineering approach, to reveal the interaction mechanism between STING and 5,6-dimethylxanthenone-4-acetic acid (DMXAA), an agonist that activates the TANK binding kinase 1-interferon regulatory factor 3 signaling pathway. Specifically, inspired by an analysis of the STING-DMXAA crystal structure, we designed and synthesized DMXAA derivatives to investigate the STING-DMXAA binding model. We identified that the carboxyl moiety of DMXAA was a major pharmacophore responsive to STING activation. In particular, the loss of hydrogen bond interaction between the carboxylic acid of DMXAA and the side chain Thr262 of STING led to STING inhibition. DMXAA N-methyl amide derivative (DNHM) exhibited good inhibitor activity, inhibited STING-mediated interferon production in vitro and in vivo, and effectively attenuated STING-associated inflammatory diseases. Therefore, we provide a new insight into STING-ligand interactions, which may improve the understanding of STING biology.