Two-dimensional coordination risedronate-manganese nanobelts as adjuvant for cancer radiotherapy and immunotherapy.

The irradiated tumor itself represents an opportunity to establish endogenous in situ vaccines. However, such in situ cancer vaccination (ISCV) triggered by radiation therapy (RT) alone is very weak and hardly elicits systemic anticancer immunity. In this study, we develop two-dimensional risedronate-manganese nanobelts (RMn-NBs) as an adjuvant for RT to address this issue. RMn-NBs exhibit good T2 magnetic resonance imaging performance and enhanced Fenton-like catalytic activity, which induces immunogenic cell death. RMn-NBs can inhibit the HIF-1α/VEGF axis to empower RT and synchronously activate the cGAS/STING pathway for promoting the secretion of type I interferon, thereby boosting RT-triggered ISCV and immune checkpoint blockade therapy against primary and metastatic tumors. RMn-NBs as a nano-adjuvant for RT show good biocompatibility and therapeutic efficacy, presenting a promising prospect for cancer radiotherapy and immunotherapy.

Non-discriminating engineered masking of immuno-evasive ligands on tumour-derived extracellular vesicles enhances tumour vaccination outcomes.

The success of personalized cancer immunotherapy depends on the initial tumour antigenic presentation to dendritic cells and macrophages. Tumour-derived extracellular vesicles (TEVs) contain abundant tumour antigenic molecules. The presence of anti-phagocytotic signals such as cluster of differentiation 47 (CD47) on the surface of the TEVs, however, leads to evasion of the same dendritic cells and macrophages. Here we show that iron oxide hydroxide nanocomposites can successfully mask TEV surfaces and unblock phagocytosis without affecting extracellular vesicles' elicited immune goals. After internalization, the mask disintegrates in the lysosome, releasing the tumour antigenic cargo. This triggers antigen presentation and promotes dendritic cell activation and maturation and macrophage reprogramming in animal models, leading to a drastic reduction of tumour volume and metastasis, and in human malignant pleural effusion clinical samples. This straightforward masking strategy eliminates the ubiquitous anti-phagocytosis block found in clinical samples and can be applied universally across all patient-specific TEVs as tumour antigenic agents for enhanced immunotherapy.

Synergistic immunotherapy with a calcium-based nanoinducer: evoking pyroptosis and remodeling tumor-associated macrophages for enhanced antitumor immune response.

The challenges posed by low immunogenicity and the immunosuppressive tumor microenvironment (TME) significantly hinder the efficacy of cancer immunotherapy. Pyroptosis, characterized as a pro-inflammatory cell death pathway, emerges as a promising approach to augment immunotherapy by promoting immunogenic cell death (ICD). The predominance of M2 phenotype tumor-associated macrophages (TAMs) in the TME underscores the critical need for TAM reprogramming to mitigate this immunosuppression. Herein, we introduce a calcium-based, intelligent-responsive nanoinducer (CaZCH NPs), designed to concurrently initiate pyroptosis and remodel TAMs, thereby amplifying antitumor immunotherapy effects. Modified with hyaluronic acid, CaZCH NPs can target tumor cells. Once internalized, CaZCH NPs respond to the acidic environment, releasing Ca2+, curcumin and H2O2 to induce mitochondrial Ca2+ overload and oxidation stress, leading to caspase-3/GSDME-mediated cell pyroptosis. Concurrently, O2 produced by CaZCH and pro-inflammatory cytokines from pyroptotic cells work together to shift TAM polarization towards the M1 phenotype, effectively countering TME's immunosuppressive effect. Notably, the synergistic effect of Ca2+-mediated pyroptosis and TAM remodeling demonstrates superior antitumor efficiency in colorectal cancer models. The induced ICD, coupled with M1-type TAMs, effectively enhances immunogenicity and mitigates immunosuppression, promoting dendritic cell maturation and activating CD8+ T cell-dependent systemic antitumor immunity. Our study presents a promising synergistic strategy for achieving highly efficient immunotherapy using a simple calcium-based nanoinducer.

Advances in therapeutic cancer vaccines: Harnessing immune adjuvants for enhanced efficacy and future perspectives.

Preventive cancer vaccines are highly effective in preventing viral infection-induced cancer, but advances in therapeutic cancer vaccines with a focus on eliminating cancer cells through immunotherapy are limited. To develop therapeutic cancer vaccines, the integration of optimal adjuvants is a potential strategy to enhance or complement existing therapeutic approaches. However, conventional adjuvants do not satisfy the criteria of clinical trials for therapeutic cancer vaccines. To improve the effects of adjuvants in therapeutic cancer vaccines, effective vaccination strategies must be formulated and novel adjuvants must be identified. This review offers an overview of the current advancements in therapeutic cancer vaccines and highlights in situ vaccination approaches that can be synergistically combined with other immunotherapies by harnessing the adjuvant effects. Additionally, the refinement of adjuvant systems using cutting-edge technologies and the elucidation of molecular mechanisms underlying immunogenic cell death to facilitate the development of innovative adjuvants have been discussed.

The recent advancements in protein nanoparticles for immunotherapy.

In recent years, the advancement of nanoparticle-based immunotherapy has introduced an innovative strategy for combatting diseases. Compared with other types of nanoparticles, protein nanoparticles have obtained substantial attention owing to their remarkable biocompatibility, biodegradability, ease of modification, and finely designed spatial structures. Nature provides several protein nanoparticle platforms, including viral capsids, ferritin, and albumin, which hold significant potential for disease treatment. These naturally occurring protein nanoparticles not only serve as effective drug delivery platforms but also augment antigen delivery and targeting capabilities through techniques like genetic modification and covalent conjugation. Motivated by nature's originality and driven by progress in computational methodologies, scientists have crafted numerous protein nanoparticles with intricate assembly structures, showing significant potential in the development of multivalent vaccines. Consequently, both naturally occurring and de novo designed protein nanoparticles are anticipated to enhance the effectiveness of immunotherapy. This review consolidates the advancements in protein nanoparticles for immunotherapy across diseases including cancer and other diseases like influenza, pneumonia, and hepatitis.

A photo-responsive self-healing hydrogel loaded with immunoadjuvants and MoS2 nanosheets for combating post-resection breast cancer recurrence.

Tumor recurrence after surgical resection remains a significant challenge in breast cancer treatment. Immune checkpoint blockade therapy, as a promising alternative therapy, faces limitations in combating tumor recurrence due to the low immune response rate. In this study, we developed an implantable photo-responsive self-healing hydrogel loaded with MoS2 nanosheets and the immunoadjuvant R837 (PVA-MoS2-R837, PMR hydrogel) for in situ generation of tumor-associated antigens at the post-surgical site of the primary tumor, enabling sustained and effective activation of the immune response. This PMR hydrogel exhibited potential for near-infrared (NIR) light response, tissue adhesion, self-healing, and sustained adjuvant release. When implanted at the site after tumor resection, NIR irradiation triggered a photothermal effect, resulting in the ablation of residual cancer cells. The in situ-generated tumor-associated antigens promoted dendritic cell (DC) maturation. In a mouse model, PMR hydrogel-mediated photothermal therapy combined with immune checkpoint blockade effectively inhibited the recurrence of resected tumors, providing new insights for combating post-resection breast cancer recurrence.

Programmed Nanocloak of Commensal Bacteria-Derived Nanovesicles Amplify Strong Immunoreactivity against Tumor Growth and Metastatic Progression.

Recent discoveries in commensal microbiota demonstrate the great promise of intratumoral bacteria as attractive molecular targets of tumors in improving cancer treatment. However, direct leveraging of in vivo antibacterial strategies such as antibiotics to potentiate cancer therapy often leads to uncertain effectiveness, mainly due to poor selectivity and potential adverse effects. Here, building from the clinical discovery that patients with breast cancer featured rich commensal bacteria, we developed an activatable biointerface by encapsulating commensal bacteria-derived extracellular vesicles (BEV) with a responsive nanocloak to potentiate immunoreactivity against intratumoral bacteria and breast cancer. We show that the interfacially cloaked BEV (cBEV) not only overcame serious systemic side responses but also demonstrated heightened immunogenicity by intercellular responsive immunogenicity, facilitating dendritic cell maturation through activating the cGAS-STING pathway. As a preventive measure, vaccination with nanocloaked cBEVs achieved strong protection against bacterial infection, largely providing prophylactic efficiency against tumor challenges. When treated in conjunction with immune checkpoint inhibitor anti-PD-L1 antibodies, the combined approach elicited a potent tumor-specific immune response, synergistically inhibiting tumor progression and mitigating lung metastases.

Mitochondria-Targeting and Oxygen Self-Supplying Eccentric Hollow Nanoplatform for Enhanced Breast Cancer Photodynamic Therapy.

Photodynamic therapy (PDT) has received increasing attention for tumor therapy due to its minimal invasiveness and spatiotemporal selectivity. However, the poor targeting of photosensitizer and hypoxia of the tumor microenvironment limit the PDT efficacy. Herein, eccentric hollow mesoporous organic silica nanoparticles (EHMONs) are prepared by anisotropic encapsulation and hydrothermal etching for constructing PDT nanoplatforms with targeting and hypoxia-alleviating properties. The prepared EHMONs possess a unique eccentric hollow structure, a uniform size (300 nm), a large cavity, and ordered mesoporous channels (2.3 nm). The EHMONs are modified with the mitochondria-targeting molecule triphenylphosphine (CTPP) and photosensitizers chlorin e6 (Ce6). Oxygen-carrying compound perfluorocarbons (PFCs) are further loaded in the internal cavity of EHMONs. Hemolytic assays and in vitro toxicity experiments show that the EHMONs-Ce6-CTPP possesses very good biocompatibility and can target mitochondria of triple-negative breast cancer, thus increasing the accumulation of photosensitizers Ce6 at mitochondria after entering cancer cells. The EHMONs-Ce6-CTPP@PFCs with oxygen-carrying ability can alleviate hypoxia after entering in the cancer cell. Phantom and cellular experiments show that the EHMONs-Ce6-CTPP@PFCs produce more singlet oxygen reactive oxygen species (ROSs). Thus, in vitro and in vivo experiments demonstrated that the EHMONs-Ce6-CTPP@PFCs showed excellent treatment effects for triple-negative breast cancer. This research provides a new method for a targeting and oxygen-carrying nanoplatform for enhancing PDF effectiveness.

Emerging nanomaterials targeting macrophage adapted to abnormal metabolism in cancer and atherosclerosis therapy (Review).

Macrophages, as highly heterogeneous and plastic immune cells, occupy a pivotal role in both pro­inflammatory (M1) and anti­inflammatory (M2) responses. While M1­type macrophages secrete pro­inflammatory factors to initiate and sustain inflammation, M2­type macrophages promote inflammation regression and uphold tissue homeostasis. These distinct phenotypic transitions in macrophages are closely linked to significant alterations in cellular metabolism, encompassing key response pathways such as glycolysis, pentose phosphate pathway, oxidative phosphorylation, lipid metabolism, amino acid metabolism, the tricarboxylic acid cycle and iron metabolism. These metabolic adaptations enable macrophages to adapt their activities in response to varying disease microenvironments. Therefore, the present review focused primarily on elucidating the intricate metabolic pathways that underlie macrophage functionality. Subsequently, it offers a comprehensive overview of the current state­of­the­art nanomaterials, highlighting their promising potential in modulating macrophage metabolism to effectively hinder disease progression in both cancer and atherosclerosis.

Ultrasensitive Electrochemiluminescence Immunosensor for Bladder Marker Human Complement Factor H-Related Protein Detection.

The development of noninvasive and sensitive detection methods for the early diagnosis and monitoring of bladder cancer is critical but challenging. Herein, an ultrasensitive electrochemiluminescence (ECL) immunosensor that uses Ru(bpy)32+-metal-organic framework (Ru-MOF) nanospheres and a DNA tetrahedral (TDN) probe was established for bladder cancer marker complement factor H-related protein (CFHR1) detection. The synthesized Ru(bpy)32+-metal-organic frameworks (Ru-MOFs) served as a linked substrate for immobilization of AuNPs and antibody (Ab2) to prepare the ECL signal probe (Ru-MOF@AuNPs-Ab2), exhibiting a stable and strengthened ECL emission. At the same time, the inherent advantages of TDN probes on the electrode as the capture probe (TDN-Ab1) improve the accessibility of targets to probes. In the presence of CFHR1, the signal probe Ru-MOF@AuNPs-Ab2 was modified on the electrode through immune binding, thereby obtaining an outstanding ECL signal. As expected, the developed ECL immunosensor exhibited splendid performance for CFHR1 detection in the range of 0.1 fg/mL to 10 pg/mL with a quite low detection limit of 0.069 fg/mL. By using the proposed strategy to detect CFHR1 from urine, it showed acceptable accuracy, which can effectively distinguish between bladder cancer patients and healthy samples. This work contributes to a novel, noninvasive, and accurate method for early clinical diagnosis of bladder cancer.

Interactions of Nanomaterials with Gut Microbiota and Their Applications in Cancer Therapy.

Cancer treatment is a challenge by its incredible complexity. As a key driver and player of cancer, gut microbiota influences the efficacy of cancer treatment. Modalities to manipulate gut microbiota have been reported to enhance antitumor efficacy in some cases. Nanomaterials (NMs) have been comprehensively applied in cancer diagnosis, imaging, and theranostics due to their unique and excellent properties, and their effectiveness is also influenced by gut microbiota. Nanotechnology is capable of targeting and manipulating gut microbiota, which offers massive opportunities to potentiate cancer treatment. Given the complexity of gut microbiota-host interactions, understanding NMs-gut interactions and NMs-gut microbiota interactions are important for applying nanotechnologies towards manipulating gut microbiota in cancer prevention and treatment. In this review, we provide an overview of NMs-gut interactions and NMs-gut microbiota interactions and highlight the influences of gut microbiota on the diagnosis and treatment effects of NMs, further illustrating the potential of nanotechnologies in cancer therapy. Investigation of the influences of NMs on cancer from the perspective of gut microbiota will boost the prospect of nanotechnology intervention of gut microbiota for cancer therapy.

Paintable Bioactive Extracellular Vesicle Ink for Wound Healing.

The treatment of cutaneous wounds involving complex biological processes has become a significant public health concern worldwide. Here, we developed an efficient extracellular vesicle (EV) ink to regulate the inflammatory microenvironment and promote vascular regeneration for wound healing. The technology, termed portable bioactive ink for tissue healing (PAINT), leverages bioactive M2 macrophage-derived EVs (EVM2) and a sodium alginate precursor, forming a biocompatible EV-Gel within 3 min after mixing, enabling it to be smeared on wounds in situ to meet diverse morphologies. The bioactive EVM2 reprogram macrophage polarization and promote the proliferation and migration of endothelial cells, thereby effectively regulating inflammation and enhancing angiogenesis in wounds. Through integration with a 3D printing pen, the platform enables EV-Gel to be applied to wound sites having arbitrary shapes and sizes with geometric matches for tissue repairment. When evaluated using a mouse wound model, PAINT technology accelerates cutaneous wound healing by promoting the angiogenesis of endothelial cells and the polarization of macrophages to M2 phenotype in vivo, demonstrating the high potential of bioactive EV ink as a portable biomedical platform for healthcare.

Spatiotemporal Monitoring of Subcellular mRNAs In Situ via Polyadenine-Mediated Dual-Color Sticky Flares.

Spatiotemporal monitoring of multiple low-abundance messenger RNAs (mRNAs) is vitally important for the diagnosis and pathologic analysis of cancer. However, it remains a clinical challenge to monitor and track multiple mRNAs location simultaneously in situ at subcellular level with high efficiency. Herein, we proposed polyA-mediated dual-color sticky flares for simultaneous imaging of two kinds of intracellular mRNA biomarkers. Two kinds of fluorescent DNA specific for GalNac-T mRNA and c-Myc mRNA were functionalized onto gold nanoparticles (AuNPs) through efficient polyadenine (polyA) attachment. By tuning polyA length, the lateral spacing and densities of DNA on AuNPs could be precisely engineered. Compared to the traditional thio-DNA-modified nanoprobes, the uniformity, detection sensitivity, and response kinetics of sticky flares were greatly improved, which enables live-cell imaging of mRNAs with enhanced efficiency. With a sticky-end design, the fluorescent DNA could dynamically trace mRNAs after binding with target mRNAs, which realized spatiotemporal monitoring of subcellular mRNAs in situ. Compared to one target mRNA imaging mode, the multiple target imaging mode allows more accurate diagnosis of cancer. Furthermore, the proposed polyA-mediated dual-color sticky flares exhibit excellent cell entry efficiency and low cytotoxicity with a low-cost and simple assembling process, which provide a pivotal tool for multiple targets imaging in living cells.

Flexible human serum albumin nanocapsules to enhance drug delivery and cellular uptake for photodynamic/chemo cancer therapy.

As a non-invasive cancer treatment, photodynamic therapy (PDT) has great applications in superficial tumors because of its high selectivity and low cumulative toxicity. However, the poor tumor-targeting ability and short blood circulation time of conventional photosensitizers (PSs) limit the efficacy of PDT to some extent. In this study, we synthesized flexible hollow human serum albumin (HHSA) and loaded photosensitizer Chlorin e6 (Ce6) and the chemotherapeutic drug Doxorubicin (DOX) for synergistic cancer therapy. HHSA can enhance drug delivery and cellular uptake through targeting gp60 and SPARC receptors and unique flexible hollow structures. The TEM images show that HHSA possesses distinct flexible hollow structures, as well as good monodispersity and deformability. After loading Ce6 and DOX, HHSA@Ce6-DOX displays better therapeutic effects than HHSA@DOX on the growth of 4T1 breast cancers without irradiation. Remarkably, it has a significantly higher therapeutic effect (relative cell activity: 45% vs. 74%) than HHSA@Ce6 under 660 nm irradiation. Furthermore, the excellent biocompatibility of HHSA@Ce6-DOX has been proved both in vitro and in vivo, indicating that it has a promising future in synergistic tumor treatments.

Flexible Hollow Human Serum Albumin-Catalase Nanocapsules with High Accumulation and Uptake Ability for Enhanced Photodynamic Therapy.

Introduction: Photodynamic therapy (PDT) has attracted increasing attention for tumor treatment because of its minimal invasiveness and specific spatiotemporal selectivity. However, insufficient tumor accumulation and low cellular uptake of photosensitizers limit its therapeutic efficacy. Methods: In this study, flexible hollow human serum albumin/catalase nanocapsules (HSA/CATs) were created using a core-assisted protein-coating method and combined with the photosensitizer chlorin e6 (HSA/CAT@Ce6) for PDT. Results and Discussion: Transmission electron microscopy (TEM) images demonstrate that HSA/CAT nanocapsules are flexible, with a uniform diameter (310 nm) and a well-defined hollow structure. Thanks to their flexibility, HSA/CAT@Ce6 nanocapsules show a higher cellular uptake than rigid nanoparticles. The nanocapsules effectively generate reactive oxygen species (ROS) in 4T1 cells because of their high cellular uptake and catalytic capacity, remarkably enhancing their in vitro PDT efficacy. In addition, the in vivo tumor accumulation of HSA/CAT@Ce6 nanocapsules is significantly larger than that of rigid nanoparticles and Ce6, meaning they are highly effective in tumor cell ablation. This demonstrates that our flexible nanoplatform holds great promise for enhancing PDT of tumor.

Elasticity of mesoporous nanocapsules regulates cellular uptake, blood circulation, and intratumoral distribution.

The elasticity of nanoparticles plays a critical role in regulating nanoparticle-biosystem interactions. However, the elasticity of traditional organic-based carriers can only be regulated within a narrow range, and the effects of elasticity on in vivo biological processes have not been evaluated until now. Here, we construct hyaluronic acid modified mesoporous organosilica nanoparticles (MONs-HA) with a wide range of elasticity by an interior preferential etching approach and investigate the impact of their elasticity on in vitro cellular uptake, in vivo blood circulation, and tumor accumulation. The Young's moduli of the prepared MONs-HA are 1.64, 0.93, 0.78, 0.4 and 0.29 GPa (denoted as rigid MONs0-HA, semi-elastic MONs20-HA and MONs50-HA, elastic MONs100-HA and MONs200-HA), respectively. They all possess a similar hydrodynamic size (245-257 nm), similar surface electronegativity (-27 to -35 mV), and excellent dispersibility. In vitro experiments demonstrate that the elastic MONs100-HA and MONs200-HA (0.4 and 0.29 GPa) exhibit significantly greater cellular uptake relative to semi-elastic MONs20-HA and MONs50-HA (0.93 and 0.78 GPa) or rigid MONs0-HA (1.64 GPa). Simultaneously, these elastic MONs100-HA and MONs200-HA show an efficiently prolonged circulation time. In vivo results revealed that the elastic MONs100-HA show enhanced tumor accumulation compared to semi-elastic and rigid MONs-HA after intravenous administration. These desirable features of elasticity can direct the design of nanoplatforms, leading to an enhanced tumor delivery efficiency.

Emerging Strategies of Engineering and Tracking Dendritic Cells for Cancer Immunotherapy.

Dendritic cells (DCs), a kind of specialized immune cells, play key roles in antitumor immune response and promotion of innate and adaptive immune responses. Recently, many strategies have been developed to utilize DCs in cancer therapy, such as delivering antigens and adjuvants to DCs and using scaffold to recruit and activate DCs. Here we outline how different DC subsets influence antitumor immunity, summarize the FDA-approved vaccines and cancer vaccines under clinical trials, discuss the strategies for engineering DCs and noninvasive tracking of DCs to improve antitumor immunotherapy, and reveal the potential of artificial neural networks for the design of DC based vaccines.

Gadolinium-hybridized mesoporous organosilica nanoparticles with high magnetic resonance imaging performance for targeted drug delivery.

Magnetic resonance (MR) imaging techniques, which can provide images with excellent anatomical detail, are widely used in clinical diagnosis. However, the current clinical small molecule gadolinium (Gd) contrast agents have the defects of relatively low sensitivity and poor tumor-target specificity, preventing their adoption in biology and medicine. Herein, a facile synthetic strategy to fabricate gadolinium-hybridized mesoporous organosilica nanoparticles (MOSG) through a nanoprecipitation reaction, with the surface of nanoparticles grafted with the fluorescent dye isothiocyanate (FITC) and arginine-glycine-aspartic acid (RGD) for delivery of the antitumour drug doxorubicin hydrochloride (DOX), resulting in a high-performance nanotheranostic (RGD-MOSG-FITC/DOX) for targeted magnetic resonance imaging and chemotherapy of tumors. The prepared MOSG had a particle size of 60-80 nm and gadolinium elements were distributed in clusters that exhibited boosted longitudinal relaxivity. Routine blood tests and histopathology indicated good biocompatibility of MOSG. Furthermore, after being decorated with Arg-Gly-Asp peptide (RGD), RGD-MOSG-FITC demonstrated more preferable cellular uptake by HeLa cells (high expression of αⅤß3) than MOSG without RGD grafting. Additionally, the tumor growth inhibition effect of RGD-MOSG-FITC/DOX was substantially more effective than that of the other groups. Therefore, this new delivery platform has good application potential in the field of tumor diagnosis and treatment.

Biomimetic 3D Recognition with 2D Flexible Nanoarchitectures for Ultrasensitive and Visual Extracellular Vesicle Detection.

Despite increasing recognition of extracellular vesicles being important circulating biomarkers in disease diagnosis and prognosis, current strategies for extracellular vesicle detection remain limited due to the compromised sample purification and extensive labeling procedures in complex body fluids. Here, we developed a 2D magnetic platform that greatly improves capture efficiency and readily realizes visible signal conversion for extracellular vesicle detection. The technology, termed high-affinity recognition and visual extracellular vesicle testing (HARVEST), leverages 2D flexible Fe3O4-MoS2 nanostructures to recognize extracellular vesicles through multidentate affinity binding and feasible magnetic separation, thus enhancing the extracellular vesicle capture performance with both yield and separation time, affording high sensitivity with the detection limit of 20 extracellular vesicle particles/µL. Through integration with lipid labeling chemistry and the fluorescence visualization system, the platform enables rapid and visible detection. The number of extracellular vesicles can be feasibly determined by smart mobile phones, readily adapted for point-of-care diagnosis. When clinically evaluated, the strategy accurately differentiates melanoma samples from the normal cohort with an AUC of 0.98, demonstrating the efficient extracellular vesicle detection strategy with 2D flexible platforms for cancer diagnosis.

Intracellular miRNA-Triggered Surface-Enhanced Raman Scattering Imaging and Dual Gene-Silencing Therapy of Cancer Cell.

Development of theranostic nanosystems integrating cascaded surface-enhanced Raman scattering (SERS) imaging and gene silencing therapy for accurate cancer diagnosis and treatment is still a big challenge and rarely reported. Herein, a novel Au nanoparticles (AuNPs)-based theranostic nanosystem containing AuNP-Ys and AuNP-Ds for highly sensitive and specific cancer diagnosis and treatment was proposed for cascaded SERS imaging of intracellular cancer-related miR-106a and miR-106a-triggered DNAzyme-based dual gene-silencing therapy of cancer cells. The AuNP-Ys were prepared by modifying the AuNPs with specially designed Y-motifs, and the AuNP-Ds were obtained by colabeling Raman molecules and dsDNA linkers on AuNPs. When identifying the intracellular cancer-related miRNAs, the Y-motifs and dsDNA linkers undergoes miRNA-triggered ATP-driven conformational transitions and releases the miRNA for recycling, which results in the formation of AuNP network nanostructures to generate significantly enhanced SERS signals for sensitive identification of the cancer cells as well as the amplification and specific activation of DNAzymes to catalyze the Mg2+-assisted cleavage of the Survivin and c-Jun mRNAs for effective dual gene-silencing therapy of cancer cells. The AuNP-based theranostic nanosystem achieves the synergism of target-triggered SERS imaging and DNAzyme-based dual gene-silencing therapy with enhanced specificity, sensitivity, and curative effect, which can be a powerful tool for accurate diagnosis and efficient treatment of cancers.