Structural Defect-Enabled Magnetic Neutrality Nanoprobes for Ultra-High-Field Magnetic Resonance Imaging of Isolated Tumor Cells in Vivo.

The identification of metastasis "seeds," isolated tumor cells (ITCs), is of paramount importance for the prognosis and tailored treatment of metastatic diseases. The conventional approach to clinical ITCs diagnosis through invasive biopsies is encumbered by the inherent risks of overdiagnosis and overtreatment. This underscores the pressing need for noninvasive ITCs detection methods that provide histopathological-level insights. Recent advancements in ultra-high-field (UHF) magnetic resonance imaging (MRI) have ignited hope for the revelation of minute lesions, including the elusive ITCs. Nevertheless, currently available MRI contrast agents are susceptible to magnetization-induced strong T2-decaying effects under UHF conditions, which compromises T1 MRI capability and further impedes the precise imaging of small lesions. Herein, this study reports a structural defect-enabled magnetic neutrality nanoprobe (MNN) distinguished by its paramagnetic properties featuring an exceptionally low magnetic susceptibility through atomic modulation, rendering it almost nonmagnetic. This unique characteristic effectively mitigates T2-decaying effect while concurrently enhancing UHF T1 contrast. Under 9 T MRI, the MNN demonstrates an unprecedentedly low r2/r1 value (≈1.06), enabling noninvasive visualization of ITCs with an exceptional detection threshold of ≈0.16 mm. These high-performance MNNs unveil the domain of hitherto undetectable minute lesions, representing a significant advancement in UHF-MRI for diagnostic purposes and fostering comprehensive metastasis research.

DNA-Mediated Magnetic-Dimer Assembly for Fault-Free Ultra-High-Field Magnetic Resonance Imaging of Tumors.

Ultra-high-field (UHF) magnetic resonance imaging (MRI) stands as a pivotal cornerstone in biomedical imaging, yet the challenge of false imaging persists, constraining its full potential. Despite the development of dual-mode contrast agents improving conventional MRI, their effectiveness in UHF remains suboptimal due to the high magnetic moment, resulting in diminished T1 relaxivity and excessively enhanced T2 relaxivity. Herein, we report a DNA-mediated magnetic-dimer assembly (DMA) of iron oxide nanoparticles that harnesses UHF-tailored nanomagnetism for fault-free UHF-MRI. DMA exhibits a dually enhanced longitudinal relaxivity of 4.42 mM-1·s-1 and transverse relaxivity of 26.23 mM-1·s-1 at 9 T, demonstrating a typical T1-T2 dual-mode UHF-MRI contrast agent. Importantly, DMA leverages T1-T2 dual-modality image fusion to achieve artifact-free breast cancer visualization, effectively filtering interference from hundred-micrometer-level false-positive signals with unprecedented precision. The UHF-tailored T1-T2 dual-mode DMA contrast agents hold promise for elevating the accuracy of MR imaging in disease diagnosis.

Ligand-Induced Atomically Segregation-Tunable Alloy Nanoprobes for Enhanced Magnetic Resonance Imaging.

Bimetallic iron-noble metal alloy nanoparticles have emerged as promising contrast agents for magnetic resonance imaging (MRI) due to their biocompatibility and facile control over the element distribution. However, the inherent surface energy discrepancy between iron and noble metal often leads to Fe atom segregation within the nanoparticle, resulting in limited iron-water molecule interactions and, consequently, diminished relaxometric performance. In this study, we present the development of a class of ligand-induced atomically segregation-tunable alloy nanoprobes (STAN) composed of bimetallic iron-gold nanoparticles. By manipulating the oxidation state of Fe on the particle surface through varying molar ratios of oleic acid and oleylamine ligands, we successfully achieve surface Fe enrichment. Under the application of a 9 T MRI system, the optimized STAN formulation, characterized by a surface Fe content of 60.1 at %, exhibits an impressive r1 value of 2.28 mM-1·s-1, along with a low r2/r1 ratio of 6.2. This exceptional performance allows for the clear visualization of hepatic tumors as small as 0.7 mm in diameter in vivo, highlighting the immense potential of STAN as a next-generation contrast agent for highly sensitive MR imaging.

Catalytic Dual-Mode Immunotherapy: Anisotropic AuPt Heterostructure Decorated with Starry Pt Nanoclusters for Robust Cancer Photometalloimmunotherapy.

To overcome current limitations in photoimmunotherapy, such as insufficient tumor antigen generation and a subdued immune response, a novel photo-/metallo dual-mode immunotherapeutic agent (PMIA) is introduced for potent near-infrared (NIR) light-triggered cancer therapy. PMIA features a dumbbell-like AuPt heterostructure decorated with starry Pt nanoclusters, meticulously engineered for enhancing plasmonic catalysis through multi-dimensional regulation of Pt growth on Au nanorods. Under NIR laser exposure, end-tipped Pt nanoclusters induce efficient electron-hole spatial separation along the longitudinal axis, resulting in radial and axial electron distribution polarization, conferring unique anisotropic properties to PMIA. Additionally, starry Pt nanoclusters on the sides of Au nanorods augment the local electron enrichment field. Validated through finite-difference time-domain analysis and Raman scattering, this configuration fosters local electron enrichment, facilitating robust reactive oxygen species generation for potent photoimmunotherapy. Moreover, Pt nanoclusters facilitate Pt2+ ion release, instigating intranuclear DNA damage and inducing synergistic immunogenic cell death (ICD) for metalloimmunotherapy. Consequently, PMIA elicits abundant danger-associated molecular patterns, promotes T cell infiltration, and triggers systemic immune responses, effectively treating primary and distant tumors, inhibiting metastasis in vivo. This study unveils a pioneering dual-mode ICD amplification strategy driven by NIR light, synergistically integrating photoimmunotherapy and metalloimmunotherapy, culminating in potent cancer photometalloimmunotherapy.

Disrupting glycolysis and DNA repair in anaplastic thyroid cancer with nucleus-targeting platinum nanoclusters.

Cancer cells rely on aerobic glycolysis and DNA repair signals to drive tumor growth and develop drug resistance. Yet, fine-tuning aerobic glycolysis with the assist of nanotechnology, for example, dampening lactate dehydrogenase (LDH) for cancer cell metabolic reprograming remains to be investigated. Here we focus on anaplastic thyroid cancer (ATC) as an extremely malignant cancer with the high expression of LDH, and develop a pH-responsive and nucleus-targeting platinum nanocluster (Pt@TAT/sPEG) to simultaneously targets LDH and exacerbates DNA damage. Pt@TAT/sPEG effectively disrupts LDH activity, reducing lactate production and ATP levels, and meanwhile induces ROS production, DNA damage, and apoptosis in ATC tumor cells. We found Pt@TAT/sPEG also blocks nucleotide excision repair pathway and achieves effective tumor cell killing. In an orthotopic ATC xenograft model, Pt@TAT/sPEG demonstrates superior tumor growth suppression compared to Pt@sPEG and cisplatin. This nanostrategy offers a feasible approach to simultaneously inhibit glycolysis and DNA repair for metabolic reprogramming and enhanced tumor chemotherapy.

An artificial protein modulator reprogramming neuronal protein functions.

Reversible protein phosphorylation, regulated by protein phosphatases, fine-tunes target protein function and plays a vital role in biological processes. Dysregulation of this process leads to aberrant post-translational modifications (PTMs) and contributes to disease development. Despite the widespread use of artificial catalysts as enzyme mimetics, their direct modulation of proteins remains largely unexplored. To address this gap and enable the reversal of aberrant PTMs for disease therapy, we present the development of artificial protein modulators (APROMs). Through atomic-level engineering of heterogeneous catalysts with asymmetric catalytic centers, these modulators bear structural similarities to protein phosphatases and exhibit remarkable ability to destabilize the bridging µ3-hydroxide. This activation of catalytic centers enables spontaneous hydrolysis of phospho-substrates, providing precise control over PTMs. Notably, APROMs, with protein phosphatase-like characteristics, catalytically reprogram the biological function of α-synuclein by directly hydrolyzing hyperphosphorylated α-synuclein. Consequently, synaptic function is reinforced in Parkinson's disease. Our findings offer a promising avenue for reprogramming protein function through de novo PTMs strategy.

Metal nanoparticles for cancer therapy: Precision targeting of DNA damage.

Cancer, a complex and heterogeneous disease, arises from genomic instability. Currently, DNA damage-based cancer treatments, including radiotherapy and chemotherapy, are employed in clinical practice. However, the efficacy and safety of these therapies are constrained by various factors, limiting their ability to meet current clinical demands. Metal nanoparticles present promising avenues for enhancing each critical aspect of DNA damage-based cancer therapy. Their customizable physicochemical properties enable the development of targeted and personalized treatment platforms. In this review, we delve into the design principles and optimization strategies of metal nanoparticles. We shed light on the limitations of DNA damage-based therapy while highlighting the diverse strategies made possible by metal nanoparticles. These encompass targeted drug delivery, inhibition of DNA repair mechanisms, induction of cell death, and the cascading immune response. Moreover, we explore the pivotal role of physicochemical factors such as nanoparticle size, stimuli-responsiveness, and surface modification in shaping metal nanoparticle platforms. Finally, we present insights into the challenges and future directions of metal nanoparticles in advancing DNA damage-based cancer therapy, paving the way for novel treatment paradigms.

Self-propelled assembly of nanoparticles with self-catalytic regulation for tumour-specific imaging and therapy.

Targeted assembly of nanoparticles in biological systems holds great promise for disease-specific imaging and therapy. However, the current manipulation of nanoparticle dynamics is primarily limited to organic pericyclic reactions, which necessitate the introduction of synthetic functional groups as bioorthogonal handles on the nanoparticles, leading to complex and laborious design processes. Here, we report the synthesis of tyrosine (Tyr)-modified peptides-capped iodine (I) doped CuS nanoparticles (CuS-I@P1 NPs) as self-catalytic building blocks that undergo self-propelled assembly inside tumour cells via Tyr-Tyr condensation reactions catalyzed by the nanoparticles themselves. Upon cellular internalization, the CuS-I@P1 NPs undergo furin-guided condensation reactions, leading to the formation of CuS-I nanoparticle assemblies through dityrosine bond. The tumour-specific furin-instructed intracellular assembly of CuS-I NPs exhibits activatable dual-modal imaging capability and enhanced photothermal effect, enabling highly efficient imaging and therapy of tumours. The robust nanoparticle self-catalysis-regulated in situ assembly, facilitated by natural handles, offers the advantages of convenient fabrication, high reaction specificity, and biocompatibility, representing a generalizable strategy for target-specific activatable biomedical imaging and therapy.

Ligand-Mediated Magnetism-Conversion Nanoprobes for Activatable Ultra-High Field Magnetic Resonance Imaging.

Ultra-high field (UHF) magnetic resonance imaging (MRI) has emerged as a focal point of interest in the field of cancer diagnosis. Despite the ability of current paramagnetic or superparamagnetic smart MRI contrast agents to selectively enhance tumor signals in low-field MRI, their effectiveness at UHF remains inadequate due to inherent magnetism. Here, we report a ligand-mediated magnetism-conversion nanoprobe (MCNP) composed of 3-mercaptopropionic acid ligand-coated silver-gadolinium bimetallic nanoparticles. The MCNP exhibits a pH-dependent magnetism conversion from ferromagnetism to diamagnetism, facilitating tunable nanomagnetism for pH-activatable UHF MRI. Under neutral pH, the thiolate (-S- ) ligands lead to short τ'm and increased magnetization of the MCNPs. Conversely, in the acidic tumor microenvironment, the thiolate ligands are protonated and transform into thiol (-SH) ligands, resulting in prolonged τ'm and decreased magnetization of the MCNP, thereby enhancing longitudinal relaxivity (r1) values at UHF MRI. Notably, under a 9 T MRI field, the pH-sensitive changes in Ag-S binding affinity of the MCNP lead to a remarkable (>10-fold) r1 increase in an acidic medium (pH 5.0). In vivo studies demonstrate the capability of MCNPs to amplify MRI signal of hepatic tumors, suggesting their potential as a next-generation UHF-tailored smart MRI contrast agent.

An Immunomodulatory Zinc-Alum/Ovalbumin Nanovaccine Boosts Cancer Metalloimmunotherapy Through Erythrocyte-Assisted Cascade Immune Activation.

Cancer therapeutic vaccines are powerful tools for immune system activation and eliciting protective responses against tumors. However, their efficacy has often been hindered by weak and slow immune responses. Here, the authors introduce an immunization strategy employing senescent erythrocytes to facilitate the accumulation of immunomodulatory zinc-Alum/ovalbumin (ZAlum/OVA) nanovaccines within both the spleen and solid tumors by temporarily saturating liver macrophages. This approach sets the stage for boosted cancer metalloimmunotherapy through a cascade immune activation. The accumulation of ZAlum/OVA nanovaccines in the spleen substantially enhances autophagy-dependent antigen presentation in dendritic cells, rapidly initiating OVA-specific T-cell responses against solid tumors. Concurrently, ZAlum/OVA nanovaccines accumulated in the tumor microenvironment trigger immunogenic cell death, leading to the induction of individualized tumor-associated antigen-specific T cell responses and increased T cell infiltration. This erythrocyte-assisted cascade immune activation using ZAlum/OVA nanovaccines results in rapid and robust antitumor immunity induction, holding great potential for clinical cancer metalloimmunotherapy.

Alpha-Synuclein Oligomers Driven T1-T2 Switchable Nanoprobes for Early and Accurate Diagnosis of Parkinson's Disease.

The alpha-synuclein (α-syn) oligomers hold a central role in the pathology of Parkinson's disease (PD). Achieving accurate detection of α-syn oligomers in vivo presents a promising avenue for early and accurate diagnosis of PD. Magnetic resonance imaging (MRI), with non-invasion and exceptional tissue penetration, offers a potent tool for visualizing α-syn oligomers in vivo. Nonetheless, ensuring diagnostic specificity remains a formidable challenge. Herein, a novel MRI probe (ASOSN) is introduced, which encompasses highly sensitive antiferromagnetic nanoparticles functionalized with single-chain fragment variable antibodies, endowing it with the capacity for discerning recognition and binding to α-syn oligomers and triggering a switchable T1-T2 MRI signal. Significantly, ASOSN possesses the unique capability to accurately discriminate α-syn oligomers from neuroinflammation in vivo. Moreover, ASOSN facilitates the non-invasive and precise visualizing of endogenous α-syn oligomers in living systems. This innovative design heralds the development of a non-invasive visualization strategy for α-syn oligomers, marking a pivotal advancement for early and accurate diagnosis of PD.

Gold-semiconductor nanohybrids as advanced phototherapeutics.

Phototherapeutics is gaining momentum as a mainstream treatment for cancer, with gold-semiconductor nanocomposites showing promise as potent phototherapeutic agents due to their structural tunability, biocompatibility and functional diversity. Such nanohybrids possess plasmonic characteristics in the presence of gold and the catalytic nature of semiconductor units, as well as the unexpected physicochemical properties arising from the contact interface. This perspective provides an overview of the latest research on gold-semiconductor nanocomposites for photodynamic, photothermal and photocatalytic therapy. The relationship between the spatial configuration of these nanohybrids and their practical performance was explored to deliver comprehensive insights and guidance for the design and fabrication of novel composite nanoplatforms to enhance the efficiency of phototherapeutics, promoting the development of nanotechnology-based advanced biomedical applications.

A Cancer Cell Selective Replication Stress Nano Amplifier Promotes Replication Fork Catastrophe to Overcome Radioresistance.

Replication stress (RS) induced by DNA damage plays a significant role in conferring the anticancer effects of radiotherapy and is tightly associated with radioresistance of cancer cells. Amplification of RS represents an effective approach to improving the efficacy of radiotherapy, although the development of selective RS amplifiers remains an unexplored frontier. We herein present an RS nano amplifier (RSNA) consisting of a catalytic FePt nanoparticle loaded with the chemotherapeutic doxorubicin (DOX), which selectively exacerbates RS in cancer cells by promoting replication fork (RF) catastrophe. RSNA converts the excessive reactive oxygen species (ROS) in cancer cells into oxygen, enhancing the DNA-damaging effects of radiotherapy to create more template lesions that impede RF progression in coalition with DOX. After radiation, ROS scavenging by RSNA accelerates RF progression through damaged template strands, increasing the frequency of RF collapse into double-strand breaks. Moreover, pretreatment with RSNA accumulates cancer cells in the S phase, exposing more RFs to radiation-induced RS. These effects of RSNA convergently maximize RS in cancer cells, effectively overcoming the radioresistance of cancer cells without affecting normal cells. Our study demonstrates the feasibility of selectively amplifying RS to boost radiotherapy.

Leveraging Coupling Effect-Enhanced Surface Plasmon Resonance of Ruthenium Nanocrystal-Decorated Mesoporous Silica Nanoparticles for Boosted Photothermal Immunotherapy.

Photothermal immunotherapy (PTI) has emerged as a promising approach for cancer treatment, while its efficacy is often hindered by the immunosuppressive tumor microenvironment (TME). Here, this work presents a multifunctional platform for tumor PTI based on ruthenium nanocrystal-decorated mesoporous silica nanoparticles (RuNC-MSN). By precisely regulating the distance between RuNC on MSN, this work achieves a remarkable enhancement in surface plasmon resonance of RuNC, leading to a significant improvement in the photothermal efficiency of RuNC-MSN. Furthermore, the inherent catalase-like activity of RuNC-MSN enables effective modulation of the immunosuppressive TME, thereby facilitating an enhanced immune response triggered by the photothermal effect-mediated immunogenic cell death (ICD). As a result, RuNC-MSN exhibits superior PTI performance, resulting in pronounced inhibition of primary tumor and metastasis. This study highlights the rational design of PTI agents with coupling effect-enhanced surface plasmon resonance, enabling simultaneous induction of ICD and regulation of the immunosuppressive TME, thereby significantly boosting PTI efficacy.

Biomimetic Silk Architectures Outperform Animal Horns in Strength and Toughness.

Structural biomimicry is an intelligent approach for developing lightweight, strong, and tough materials (LSTMs). Current fabrication technologies, such as 3D printing and two-photon lithography often face challenges in constructing complex interlaced structures, such as the sinusoidal crossed herringbone structure that contributes to the ultrahigh strength and fracture toughness of the dactyl club of peacock mantis shrimps. Herein, bioinspired LSTMs with laminated or herringbone structures is reported, by combining textile processing and silk fiber "welding" techniques. The resulting biomimetic silk LSTMs (BS-LSTMs) exhibit a remarkable combination of lightweight with a density of 0.6-0.9 g cm-3 , while also being 1.5 times stronger and 16 times more durable than animal horns. These findings demonstrate that BS-LSTMs are among the toughest natural materials made from silk proteins. Finite element simulations further reveal that the fortification and hardening of BS-LSTMs arise primarily from the hierarchical organization of silk fibers and mechanically transferable meso-interfaces. This study highlights the rational, cost-effective, controllable mesostructure, and transferable strategy of integrating textile processing and fiber "welding" techniques for the fabrication of BS-LSTMs with advantageous structural and mechanical properties. These findings have significant implications for a wide range of applications in biomedicine, mechanical engineering, intelligent textiles, aerospace industries, and beyond.

DNA-Driven Dynamic Assembly/Disassembly of Inorganic Nanocrystals for Biomedical Imaging.

DNA-mediated programming is emerging as an effective technology that enables controlled dynamic assembly/disassembly of inorganic nanocrystals (NC) with precise numbers and spatial locations for biomedical imaging applications. In this review, we will begin with a brief overview of the rules of NC dynamic assembly driven by DNA ligands, and the research progress on the relationship between NC assembly modes and their biomedical imaging performance. Then, we will give examples on how the driven program is designed by different interactions through the configuration switching of DNA-NC conjugates for biomedical applications. Finally, we will conclude with the current challenges and future perspectives of this emerging field. Hopefully, this review will deepen our knowledge on the DNA-guided precise assembly of NCs, which may further inspire the future development of smart chemical imaging devices and high-performance biomedical imaging probes.

Nanozyme-Integrated Thermoresponsive In Situ Forming Hydrogel Enhances Mesenchymal Stem Cell Viability and Paracrine Effect for Efficient Spinal Cord Repair.

Mesenchymal stem cell (MSC)-based therapy has emerged as a promising strategy for the treatment of spinal cord injury (SCI). However, the hostile microenvironment of SCI, which can adversely affect the survival and paracrine effect of the implanted MSCs, severely limits the therapeutic efficacy of this approach. Here, we report on a ceria nanozyme-integrated thermoresponsive in situ forming hydrogel (CeNZ-gel) that can enable dual enhancement of MSC viability and paracrine effect, leading to highly efficient spinal cord repair. The sol-gel transition property of the CeNZ-gel at body temperature ensures uniform coverage of the hydrogel in injured spinal cord tissues. Our results demonstrate that the CeNZ-gel significantly increases the viability of transplanted MSCs in the microenvironment by attenuating oxidative stress and, more importantly, promotes the secretion of angiogenic factors from MSCs by inducing autophagy of MSCs. The synergy between the oxidative stress-relieving effect of CeNZs and the paracrine effect of MSCs accelerates angiogenesis, nerve repair, and motor function recovery after SCI, providing an efficient strategy for MSC-based SCI therapy.

A Photomodulable Bacteriophage-Spike Nanozyme Enables Dually Enhanced Biofilm Penetration and Bacterial Capture for Photothermal-Boosted Catalytic Therapy of MRSA Infections.

Nanozymes, featuring intrinsic biocatalytic effects and broad-spectrum antimicrobial properties, are emerging as a novel antibiotic class. However, prevailing bactericidal nanozymes face a challenging dilemma between biofilm penetration and bacterial capture capacity, significantly impeding their antibacterial efficacy. Here, this work introduces a photomodulable bactericidal nanozyme (ICG@hMnOx ), composed of a hollow virus-spiky MnOx nanozyme integrated with indocyanine green, for dually enhanced biofilm penetration and bacterial capture for photothermal-boosted catalytic therapy of bacterial infections. ICG@hMnOx demonstrates an exceptional capability to deeply penetrate biofilms, owing to its pronounced photothermal effect that disrupts the compact structure of biofilms. Simultaneously, the virus-spiky surface significantly enhances the bacterial capture capacity of ICG@hMnOx . This surface acts as a membrane-anchored generator of reactive oxygen species and a glutathione scavenger, facilitating localized photothermal-boosted catalytic bacterial disinfection. Effective treatment of methicillin-resistant Staphylococcus aureus-associated biofilm infections is achieved using ICG@hMnOx , offering an appealing strategy to overcome the longstanding trade-off between biofilm penetration and bacterial capture capacity in antibacterial nanozymes. This work presents a significant advancement in the development of nanozyme-based therapies for combating biofilm-related bacterial infections.

A Selective Nano Cell Cycle Checkpoint Inhibitor Overcomes Leukemia Chemoresistance.

Cell cycle checkpoint activation promotes DNA damage repair, which is highly associated with the chemoresistance of various cancers including acute myeloid leukemia (AML). Selective cell cycle checkpoint inhibitors are strongly demanded to overcome chemoresistance, but remain unexplored. A selective nano cell cycle checkpoint inhibitor (NCCI: citric acid capped ultra-small iron oxide nanoparticles) that can catalytically inhibit the cell cycle checkpoint of AML to boost the chemotherapeutic efficacy of genotoxic agents is now reported. NCCI can selectively accumulate in AML cells and convert H2 O2 to • OH to cleave heat shock protein 90, leading to the degradation of ataxia telangiectasia and Rad3-related proteinand checkpoint kinase 1, and the subsequent dysfunction of the G2/M checkpoint. Consequently, NCCI revitalizes the anti-AML efficacy of cytarabine that is previously ineffective both in vitro and in vivo. This study offers new insights into designing selective cell cycle checkpoint inhibitors for biomedical applications.