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.

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.

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.

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.

Tumor microenvironment acidity modulates ROR1 to promote epithelial-mesenchymal transition and hepatocarcinoma metastasis.

The tendency of hepatocarcinoma to metastasize results in a high rate of mortality, making it a hot research topic in cancer studies. Although an acidic tumor microenvironment has been proven to promote cancer metastasis, the underlying regulatory mechanisms remain poorly defined. Here, we found that acidic conditions significantly enhanced cell migration and invasion ability in hepatocellular carcinoma, and the expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) was distinctly upregulated in acid-treated cells. In addition, siRNA-mediated knockdown of ROR1 could effectively inhibit acid-induced cell migration, invasion and epithelial-mesenchymal transition (EMT). Importantly, neutralization of acidic environments with NaHCO3 could downregulate acid-stimulated ROR1 expression, thereby retarding cell metastatic potential. Notably, the formation of metastatic nodules was significantly increased after intrapulmonary injection of acid-stimulated cancer cells, and this was inhibited by pretreating with NaHCO3. In summary, we reveal that an acidic tumor microenvironment modulates ROR1 expression to promote tumor metastasis, providing not only a better understanding of molecular mechanisms related to metastasis, but also a promising target for tumor management.

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.

Bioinspired All-in-One Three-Dimensional Dynamic CellMatrix Improves the Manufacture of Therapeutically Qualified Cells for Cell Therapy.

Despite the great promise, cell therapy still faces practical challenges because of the scarcity of a reliable cell source. Herein, a bioinspired 3D dynamic culture system (CellMatrix) with rational structure, composite and function, was developed for improving cell supply. CellMatrix was composed of unique core-shell fibers with a core of black phosphorus-incorporated fibroin and a shell of sericin, which together formed a 3D silkworm cocoon-mimicking structure via a bottom-up fabrication technique. CellMatrix not only provided optimal engineered biomimetic niche to facilitate cell growth but exhibited good photothermal conversion to dynamically regulate cell fates. Importantly, cell-CellMatrix construct could be directly implanted into defected tissues and improved tissue remodeling. Meanwhile, CellMatrix displayed good ice resistance and thermal conductivity, which maximally maintained cell viability and proliferation after the freeze-thawing process, allowing for storing precious cells and cell-CellMatrix construct. Thus, CellMatrix represents an all-in-one biomimetic platform for the culture-production-storage of therapeutically qualified cells.

Self-Assembly of Intelligent Nanoplatform for Endogenous H2S-Triggered Multimodal Cascade Therapy of Colon Cancer.

The specific in situ generation and activation of therapeutic agents with high spatiotemporal precision is expected to revolutionize cancer treatment. Here, we develop an intelligent nanoplatform (termed as NP-Cu), which is constructed by assembling photosensitizer chlorin e6 (Ce6), hypoxia-responsive prodrug banoxantrone (AQ4N) with clickable dibenzocyclooctyne (DIBO) functionalized lysine (D-K), and cyclen-Cu2+ complex, for improving combination anticancer therapy. Cyclen-Cu2+ complex-induced photodynamic therapy (PDT) quenching in NP-Cu can be effectively and selectively activated by tumor-overproduced hydrogen sulfide (H2S). More importantly, the reaction of endogenous H2S with Cu2+ can generate photothermal agent copper sulfide (CuS) for photothermal therapy (PTT). Furthermore, with the activation of PTT and PDT, intracellular hypoxic stress is amplified to trigger AQ4N-associated chemodynamic therapy (CDT), leading to light-enhanced cascade therapy of PDT, PTT and CDT. Therefore, we present a simple and practical strategy for developing pathological stimuli responsive combination therapy, which has the potential of advancing precision cancer medicine.

The First FRET-Based RNA Aptamer NanoKit for Sensitively and Specifically Detecting c-di-GMP.

An effective method to identify c-di-GMP may significantly facilitate the exploration of its signaling pathways and bacterial pathogenesis. Herein, we have developed the first conjugated polymer-amplified RNA aptamer NanoKit with a unique core-shell-shell architecture, which combines the advantages of high selectivity of RNA aptamers and high sensitivity of strong fluorescence resonance energy transfer (FRET) effect, for precisely detecting c-di-GMP. We identified that NanoKit could selectively detect c-di-GMP with a low detection limit of 50 pM. Importantly, NanoKit could identify bacterial species and physiological states, such as planktonic, biofilm, and even antibiotic-resistance, on the basis of their different c-di-GMP expression patterns. Particularly, NanoKit could distinguish bacterial infection and inflammation and identify Pseudomonas aeruginosa associated pneumonia and sepsis, thereby guiding treatment choice and monitoring antibiotic effects. Therefore, NanoKit provides a promising strategy to rapidly identify c-di-GMP and its associated diseases and may benefit for pathophoresis management.

Photoactive 3D-Printed Hypertensile Metamaterials for Improving Dynamic Modeling of Stem Cells.

Current three-dimensional (3D) cell culture systems mainly rely on static cell culture and lack the ability to thoroughly manage cell intrinsic behaviors and biological characteristics, leading to unsatisfied cell activity. Herein, we have developed photoactive 3D-printed hypertensile metamaterials based dynamic cell culture system (MetaFold) for guiding cell fate. MetaFold exhibited high elasticity and photothermal conversion efficiency due to its metapattern architecture and micro/nanoscale polydopamine coating, allowing for responding to mechanical and light stimulation to construct dynamic culture conditions. In addition, MetaFold possessed excellent cell adhesion capability and could promote cell viability and function under dynamic stimulation, thereby maximizing cell activity. Importantly, MetaFold could improve the differentiation efficacy of stem cells into cardiomyocytes and even their maturation, offering high-quality precious candidates for cell therapy. Therefore, we present a dual stimuli-responsive dynamic culture system, which provides a physiologically realistic environment for cell culture and biological study.

Biomimetic Activator of Sonodynamic Ferroptosis Amplifies Inherent Peroxidation for Improving the Treatment of Breast Cancer.

Ferroptosis is a type of nonapoptotic cell death and is gradually emerging as an important anticancer treatment. However, its therapeutic efficacy is impaired by low intracellular levels of reactive oxygen species (ROS) and long-chain polyunsaturated fatty acids, significantly limiting its therapeutic potential. Herein, a multimodal strategy to improve ferroptosis is presented, in which a state-of-art engineered erythrocyte, termed as sonodynamic amplified ferroptosis erythrocyte (SAFE), is developed for simultaneously activating ferroptosis and oxygen-riched sonodynamic therapy (SDT). SAFE is composed of internalizing RGD peptide and red blood cell membrane hybrid camouflaged nanocomplex of hemoglobin, perfluorocarbon, ferroptosis activator (dihomo-γ-linolenic acid, DGLA), and sonosensitizer verteporfin. It is identified that SAFE, under ultrasound stimulation, can not only substantially supply oxygen to overcome tumor hypoxia associated therapeutic resistance, but effectively activate ferroptosis through the coeffect of SDT triggered ROS production and DGLA mediated lipid peroxidation. In vivo studies reveal that SAFE selectively accumulates in tumor tissues and induces desirable anticancer effects under mild ultrasound stimulation. Importantly, SAFE can effectively inhibit tumor growth with minimal invasiveness, resulting in a prolonged survival period of mice. Therefore, a multimodal ferroptosis therapy driven by oxygen-riched sonodynamic peroxidation of lipids, significantly advancing synergistic cancer treatment, is presented.

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.

N-Cadherin Nanoantagonist Driven Mesenchymal-to-Epithelial Transition in Fibroblasts for Improving Reprogramming Efficiency.

Induced pluripotent stem cells (iPSCs) hold promise in revolutionizing medicine; however, their application potential is limited because of low reprogramming efficiency. Mesenchymal-to-epithelial transition (MET) has been proved to involve reprogramming of somatic cells into iPSCs, making it a promising target for enhancing generation of iPSCs. Here, we nanoengineered N-cadherin-blocking peptide ADH-1 with gold nanoparticles, generating a multivalent N-cadherin antagonist (ADH-AuNPs), for improving reprogramming efficiency through driving cell MET. ADH-AuNPs exhibited good biocompatibility and showed higher N-cadherin inhibitory activity than ADH-1 due to multivalency, thereby enhancing cell-state reprogramming toward epithelial lineages. Particularly, ADH-AuNPs improved reprogramming efficiency by more than 7-fold after introduction of four Yamanaka factors. Importantly, ADH-AuNPs generated iPSCs displayed high stemness and pluripotency in vitro and in vivo. Therefore, we provide a cooperative strategy for promoting the iPSC generation efficacy.

A Novel Luminescent "Nanochip" as a Tandem Catalytic System for Chemiluminescent Detection of Sweat Glucose.

Accurate sweat glucose detection is a promising alternative to invasive finger-prick blood tests, allowing for self-monitoring of blood glucose with good patient compliance. In this study, we have developed a tandem catalytic system, termed as a luminescent "nanochip" (LAON), which was composed of gold nanoparticles (AuNPs) and N-(aminobutyl)-N-(ethylisoluminol) (ABEI)-engineered oxygen-doped carbon nitride (O-g-C3N4), for chemiluminescent detection of sweat glucose. The LAON exhibits dual catalytic activity of glucose oxidase and peroxidase and can not only oxidize glucose to generate H2O2 but catalyze H2O2-mediated luminol chemiluminescence, resulting in sensitive detection of glucose. We identify that the LAON can precisely detect glucose with a detection limit of 0.1 µM, enabling us to measure glucose levels in different biological samples. Particularly, the LAON is capable of sensitively and accurately monitoring dynamic changes in sweat glucose during exercise. Therefore, the LAON provides an alternative approach to supersede invasive blood tests and may improve the management of diabetes mellitus.

Nanosized Phase-Changeable "Sonocyte" for Promoting Ultrasound Assessment.

Despite the ability of microbubble contrast agents to improve ultrasound diagnostic performance, their application potential is limited due to low stability, fast clearance, and poor tissue permeation. This study presents a promising nanosized phase-changeable erythrocyte (Sonocyte), composed of liposomal dodecafluoropentane coated with multilayered red blood cell membranes (RBCm), for improving ultrasound assessments. Sonocyte is the first RBCm-functionalized ultrasound contrast agent with uniform nanosized morphology, and exhibits good stability, systemic circulation, target-tissue accumulation, and even ultrasound-responsive phase transition, thereby satisfying the inherent requirement of ultrasound imaging. It is identified that Sonocyte displays similar sensitivity as microbubble SonoVue, a clinical ultrasound contrast agent, for effectively detecting normal parenchyma and hepatic necrosis. Importantly, compared with SonoVue lacking of ability to detect tumors, Sonocyte can identify tumors with high sensitivity and specificity due to superior tumor accumulation and penetration. Therefore, Sonocyte exhibits superior capabilities over SonoVue, endowing with a great clinical application potential.

Integrin αvß3-Specific Hydrocyanine for Cooperative Targeting of Glioblastoma with High Sensitivity and Specificity.

Glioblastoma is a highly malignant brain tumor with poor prognosis and survival rate because of a lack of effective diagnostic methods. Hydrocyanines are a type of reactive oxygen species (ROS)-responsive fluorescent probes, allowing for distinguishing tumor cells from normal cells based on their different intracellular levels of ROS. However, their diagnostic applications for glioblastoma have been limited because of the inability to discriminate between tumor cells and other tissues with high ROS production, leading to high false-positive diagnosis. Therefore, tumor-responsive and -specific hydrocyanines with cooperative targeting ability have great potential for improving the diagnosis and treatment of glioblastoma. Integrin αvß3 plays a critical role in the progression and angiogenesis of glioblastoma and has become a promising target for diagnosing glioblastoma. Herein, we identify a specific peptide ligand for integrin αvß3, Arg-Trp-(d-Arg)-Asn-Arg (RWrNR), which shows high binding affinity to human glioblastoma U87MG cells. Importantly, hydro-Cy5-RWrNR conjugation allowed for distinguishing U87MG cells from normal cells in response to intracellular ROS. Particularly, hydro-Cy5-RWrNR could not only selectively accumulate in orthotopic U87MG tumor with minimal background fluorescence but also effectively discriminate between glioblastoma and inflammatory tissues for the first time, leading to detection of glioblastoma in vivo with high target-to-background ratios and minimal background fluorescence. Therefore, hydro-Cy5-RWrNR is the first integrin αvß3-specific hydrocyanine probe and has great potential in precise tumor diagnosis because of its cooperative targeting of integrin αvß3 and ROS.

Synergistic Amplification of Oxidative Stress-Mediated Antitumor Activity via Liposomal Dichloroacetic Acid and MOF-Fe2.

Cancer cells are susceptible to oxidative stress; therefore, selective elevation of intracellular reactive oxygen species (ROS) is considered as an effective antitumor treatment. Here, a liposomal formulation of dichloroacetic acid (DCA) and metal-organic framework (MOF)-Fe2+ (MD@Lip) has been developed, which can efficiently stimulate ROS-mediated cancer cell apoptosis in vitro and in vivo. MD@Lip can not only improve aqueous solubility of octahedral MOF-Fe2+ , but also generate an acidic microenvironment to activate a MOF-Fe2+ -based Fenton reaction. Importantly, MD@Lip promotes DCA-mediated mitochondrial aerobic oxidation to increase intracellular hydrogen peroxide (H2 O2 ), which can be consequently converted to highly cytotoxic hydroxyl radicals (•OH) via MOF-Fe2+ , leading to amplification of cancer cell apoptosis. Particularly, MD@Lip can selectively accumulate in tumors, and efficiently inhibit tumor growth with minimal systemic adverse effects. Therefore, liposome-based combination therapy of DCA and MOF-Fe2+ provides a promising oxidative stress-associated antitumor strategy for the management of malignant tumors.

Novel Integrin αvß3-Specific Ligand for the Sensitive Diagnosis of Glioblastoma.

Integrin αvß3 is a cell adhesion molecule involved in the progression and invasion of glioblastoma, making it an attractive target for the diagnosis of glioblastoma. Although some integrin αvß3 specific ligands, such as RGD and its mimetic peptides (Cilengitide), have been devoted in detecting glioblastoma, their clinical practices have been limited due to low specificity and affinity. Herein, we have identified a linear peptide RWrNK, containing an unnatural d-arginine (r), as the integrin αvß3-specific ligand. RWrNK shows high binding affinity to integrin αvß3 with a Kd value of 1.6 nM, which is 2-fold higher than Cilengitide (3.2 nM), a well-established integrin αvß3 ligand. In addition, RWrNK can not only rapidly transport in human glioblastoma U87MG cells but effectively label U87MG tumor spheroids, compared to Cilengitide, indicating that it possesses an ability to sensitively detect glioblastoma. Importantly, RWrNK can pass through blood-brain tumor barrier (BBTB) and selectively accumulate in orthotopic U87MG tumor within 2 h, allowing for imaging glioblastoma in vivo with high sensitivity and specificity. Overall, RWrNK has the great potential in theranostic applications for glioblastoma, in consideration of its high specificity and affinity for integrin αvß3.

A Trimethoprim Conjugate of Thiomaltose Has Enhanced Antibacterial Efficacy In Vivo.

Trimethoprim is one of the most widely used antibiotics in the world. However, its efficacy is frequently limited by its poor water solubility and dose limiting toxicity. Prodrug strategies based on conjugation of oligosaccharides to trimethoprim have great potential for increasing the solubility of trimethoprim and lowering its toxicity, but they have been challenging to develop due to the sensitivity of trimethoprim to chemical modifications, and the rapid degradation of oligosaccharides in serum. In this report, we present a trimethoprim conjugate of maltodextrin termed TM-TMP, which increased the water solubility of trimethoprim by over 100 times, was stable to serum enzymes, and was active against urinary tract infections in mice. TM-TMP is composed of thiomaltose conjugated to trimethoprim, via a self-immolative disulfide linkage, and releases 4'-OH-trimethoprim (TMP-OH) after disulfide cleavage, which is a known metabolic product of trimethoprim and is as potent as trimethoprim. TM-TMP also contains a new maltodextrin targeting ligand composed of thiomaltose, which is stable to hydrolysis by serum amylases and therefore has the metabolic stability needed for in vivo use. TM-TMP has the potential to significantly improve the treatment of a wide number of infections given its high water solubility and the widespread use of trimethoprim.