The potential of the cluster regularly interspaced short palindromic repeat (CRISPR)‐associated protein 9 (Cas9)‐based therapeutic genome editing is severely hampered by the difficulties in precise ...regulation of the in vivo activity of the CRISPR‐Cas9 system. Herein, sono‐controllable and reactive oxygen species (ROS)‐sensitive sonosensitizer‐integrated metal–organic frameworks (MOFs), denoted as P/M@CasMTH1, are developed for augmented sonodynamic therapy (SDT) efficacy using the genome‐editing technology. P/M@CasMTH1 nanoparticles comprise singlet oxygen (1O2)‐generating MOF structures anchored with CRISPR‐Cas9 systems via 1O2‐cleavable linkers, which serve not only as a delivery vector of CRISPR‐Cas9 targeting MTH1, but also as a sonoregulator to spatiotemporally activate the genome editing. P/M@CasMTH1 escapes from the lysosomes, harvests the ultrasound (US) energy and converts it into abundant 1O2 to induce SDT. The generated ROS subsequently trigger cleavage of ROS‐responsive thioether bonds, thus inducing controllable release of the CRISPR‐Cas9 system and initiation of genome editing. The genomic disruption of MTH1 conspicuously augments the therapeutic efficacy of SDT by destroying the self‐defense system in tumor cells, thereby causing cellular apoptosis and tumor suppression. This therapeutic strategy for synergistic MTH1 disruption and abundant 1O2 generation provides a paradigm for augmenting SDT efficacy based on the emerging nanomedicine‐enabled genome‐editing technology.
A novel avenue to circumvent the resistance of tumor cells in conventional sonodynamic therapy is pioneered in this work, where targeted delivery and controllable release of the cluster regularly interspaced short palindromic repeat‐associated protein system is also achieved.
Despite the efficacy of current starvation therapies, they are often associated with some intrinsic drawbacks such as poor persistence, facile tumor metastasis and recurrence. Herein, we establish an ...extravascular gelation shrinkage-derived internal stress strategy for squeezing and narrowing blood vessels, occluding blood & nutrition supply, reducing vascular density, inducing hypoxia and apoptosis and eventually realizing starvation therapy of malignancies. To this end, a biocompatible composite hydrogel consisting of gold nanorods (GNRs) and thermal-sensitive hydrogel mixture was engineered, wherein GRNs can strengthen the structural property of hydrogel mixture and enable robust gelation shrinkage-induced internal stresses. Systematic experiments demonstrate that this starvation therapy can suppress the growths of PANC-1 pancreatic cancer and 4T1 breast cancer. More significantly, this starvation strategy can suppress tumor metastasis and tumor recurrence via reducing vascular density and blood supply and occluding tumor migration passages, which thus provides a promising avenue to comprehensive cancer therapy.
Prequenching and selective activation of photosensitizer (PS) are highly desired in photodynamic therapy (PDT) to avoid off-target effect due to nonspecific activation and poor targeting selectivity ...of PS. In this study, nanographene materials as a unique π-conjugated planar system for electronic transfer were employed as the robust platform for temporarily quenching of PS. Photosensitizer chlorin e6 (Ce6) was integrated onto planar structure of graphene quantum dot (GQD) or graphene oxide (GO) via a reduction cleavable disulfide linker. The formed hybrid nanosystem displayed considerable fluorescence quenching and slight phototoxicity, even under the condition of light irradiation, while the photoactivity of PS could be selectively recovered in the presence of the reducing agent. Compared with graphene oxide system with larger size (around 200 nm), GQD nanosystem exhibited significantly improved tumor accumulation via enhanced permeation and retention effect (EPR effect). The in vivo study demonstrated extremely effective suppression of tumor growth for the group treated with the GQD nanosystem with cleavable linker, revealing the promising application of the presented novel strategy.
Reprogramming the tumor immunosuppressive microenvironment is a promising strategy for improving tumor immunotherapy efficacy. The clustered regularly interspaced short palindromic repeat ...(CRISPR)/CRISPR-associated protein 9 system can be used to knockdown tumor immunosuppression-related genes. Therefore, here, a self-driven multifunctional delivery vector is constructed to efficiently deliver the CRISPR-Cas9 nanosystem for indoleamine 2,3-dioxygenase-1 (IDO1) knockdown in order to amplify immunogenic cell death (ICD) and then reverse tumor immunosuppression. Lactobacillus rhamnosus GG (LGG) is a self-driven safety probiotic that can penetrate the hypoxia tumor center, allowing efficient delivery of the CRISPR/Cas9 system to the tumor region. While LGG efficiently colonizes the tumor area, it also stimulates the organism to activate the immune system. The CRISPR/Cas9 nanosystem can generate abundant reactive oxygen species (ROS) under the ultrasound irradiation, resulting in ICD, while the produced ROS can induce endosomal/lysosomal rupture and then releasing Cas9/sgRNA to knock down the IDO1 gene to lift immunosuppression. The system generates immune responses that effectively attack tumor cells in mice, contributing to the inhibition of tumor re-challenge in vivo. In addition, this strategy provides an immunological memory effect which offers protection against lung metastasis.
Studies have shown the potential of nanomaterials for the accurate and early detection of cancer. The aim of the present study was to design and evaluate the value of prostate-specific membrane ...antigen (PSA)-targeted manganese oxide–mesoporous silica nanoparticles (Mn–Msns) for the detection of prostate cancer. Mn–Msns were prepared, and then conjugated with the PSA antibody and Cy7 to create the multimodality PSA-Mn-Msn-Cy7. Their particle size, zeta potential, stability and magnetic resonance imaging (MRI) features of the nanoparticles were characterized. Optical and MR imaging were evaluated in cell and tumor-bearing mouse models. The Mn in tissues was measured by inductively coupled plasma mass spectrometry. The fabricated nanoparticles were stable and showed good T1relaxivity. The targeted nanoparticles accumulated to a great extent in prostate cancer cells in vitro but not in noncancerous cells. In vivo studies further demonstrated a targeted distribution of PSA-Mn-Msn-Cy7 to cancer tissues as shown by high optical and T1 signals. The targeted distribution was also confirmed by determining the Mn content in the cancer tissues. Our data demonstrate that PSA targeted fluorescence and MR dual-functional nanoparticle can visualize prostate cancer and can be used as NIRF/MR contrast agents.
The small scale gap test is a very important method to study the sensitivity characteristics of a composite solid propellant under shock waves. In this paper, the small scale gap test is taken as the ...research object. The theoretical model of shock wave conduction in the small scale gap test is established. The detonation parameters of mixed explosives and the shock wave incident parameters of propellants corresponding to different sizes of inert barriers are calculated. The reliability of the method is verified by classical examples. A numerical model is established for the small scale gap test, and the critical thickness of the partition plate is obtained with a 50% probability of initiation. The results can predict the development and safe use of a high-energy composite solid propellant and provide theoretical support for the establishment of safety standards of high-energy composite solid propellants.
MXenes, a new class of two‐dimensional (2D) nanomaterials, have shown enormous potential for biological applications. Notably, the development of 2D MXenes in nanomedicine is still in its infancy. ...Herein, a distinct W1.33C i‐MXene with multiple theranostic functionalities, fast biodegradation, and satisfactory biocompatibility is explored. By designing a parent bulk laminate in‐plane ordered (W2/3Y1/3)2AlC ceramic and optionally etching aluminum (Al) and yttrium (Y) elements, 2D W1.33C i‐MXene nanosheets with ordered divacancies are efficiently fabricated. Especially, theoretical simulations reveal that W1.33C i‐MXene possesses a strong predominance of near‐infrared (NIR) absorbance. The constructed ultrathin W1.33C nanosheets feature excellent photothermal‐conversion effectiveness (32.5% at NIR I and 49.3% at NIR II) with desirable biocompatibility and fast degradation in normal tissue rather than in tumor tissue. Importantly, the multimodal‐imaging properties and photothermal‐ablation performance of W1.33C‐BSA nanosheets are systematically revealed and demonstrated both in vitro and in vivo. The underlying mechanism and regulation factors for the W1.33C‐BSA nanosheets‐induced hyperthermia ablation are also revealed by transcriptome and proteome sequencing. This work offers a paradigm that i‐MXenes achieve the tailoring biomedical applications through composition and structure design on the atomic scale.
A distinct two dimensional W1.33C i‐MXene with multiple theranostic functionalities, fast biodegradation, and satisfactory biocompatibilityhas been demonstrated. The underlying mechanism and regulation factors for the engineered W1.33C‐BSA nanosheetsinduced photothermal hyperthermia are revealed via genomics and proteomics. This work significantly expands the biomedical applications of i‐MXene‐based nanomedicines with the desirable biological effect and excellent theranostics performance.
Sonodynamic therapy (SDT), relying on the generation of reactive oxygen species (ROS), is a promising clinical therapeutic modality for the treatment of hepatocellular carcinoma (HCC) due to its ...noninvasiveness and high tissue-penetration depth, whereas the oxidative stress and antioxidative defense system in cancer cells significantly restrict the prevalence of SDT. Herein, we initially identified that NFE2L2 was immediately activated during SDT, which further inhibited SDT efficacy. To address this intractable issue, an ultrasound remote control of the cluster regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) release system (HMME@Lip-Cas9) was meticulously designed and constructed, which precisely knocks down NFE2L2 to alleviate the adverse effects and augment the therapeutic efficiency of SDT. The hematoporphyrin monomethyl ether (HMME) in this system yielded abundant ROS to damage cancer cells under ultrasound irradiation, and meanwhile the generated ROS could induce lysosomal rupture to release Cas9/single guide RNA ribonucleoprotein (RNP) and destroy the oxidative stress-defensing system, significantly promoting tumor cell apoptosis. This study provides a new paradigm for HCC management and lays the foundation for the widespread application of CRISPR/Cas9 with promising clinical translation, meanwhile developing a synergistic therapeutic modality in the combination of SDT with gene editing.
Intratumoral or intestinal microbiota correlates with tumorigenesis and progression, and microbiota regulation for reinforcing various anti‐tumor approaches is of significant importance, which, ...however, suffers from no precise regulation method and unclear underlying mechanism. Herein, a microbiome metabolism‐engineered phototherapy strategy is established, wherein Nb2C/Au nanocomposite and the corresponding phototherapy are harnessed to realize “chemical” and “physical” bacterial regulations. Flora analysis and mass spectrometry (MS) and metabonomics combined tests demonstrate that the synergistic microbiota regulations can alter the abundance, diversity of intratumoral microbiome, and disrupt metabolic pathways of microbiome and tumor microenvironment, wherein the differential singling pathways and biosynthetic necessities or metabolites that can affect tumor progression are identified. As well, anti‐TNFα is introduced to unite with bacterial regulation to synergistically mitigate bacterial‐induced inflammation, which, along with the metabolism disruptions of intratumoral microbiota and tumor microenvironment, unfreezes tumor resistance and harvests significantly‐intensified phototherapy‐based anti‐tumor outcomes against 4T1 and CT26 tumors. The clear underlying principles of microbiome‐regulated tumorigenesis and the established microbiome metabolism regulation method provide distinctive insights into tumor therapy, and can be also extended to other gut microbiome‐associated lesions interference.
A microbiome metabolism‐engineered phototherapy strategy has been established, wherein Nb2C/Au nanocomposite and the corresponding phototherapy are harnessed to realize “chemical” and “physical” bacterial regulations via altering the abundance, diversity of intratumoral microbiome, and disrupting inflammation and metabolic pathways of microbiome and tumor microenvironment.
Metal-organic framework (MOF) is an exciting class of porous biomaterials that have been considered as a carrier to store and deliver therapeutic drugs. However, similar to other nanomaterials, the ...application of MOF in clinical settings is still limited because of premature diffusion of their payloads and tissue off-targeting behavior. To overcome these challenges, we designed an MOF-based hydrogel with structurally dynamic properties, i.e., self-healing and shear-thinning, as an injectable localized drug delivery platform. The drug-encapsulating MOF hydrogel is formed through a dynamic coordination bond cross-linkage between a doxorubicin-loaded MOF (MOF@DOX) particle and a homemade bisphosphonate-modified hyaluronic acid (HA-BP) polymeric binder. The HA-BP·MOF@DOX hydrogel demonstrates pH- and ATP-responsive drug release characteristic and efficiently kills cancer cells in vitro. The animal experiments reveal that the HA-BP·MOF@DOX hydrogel has enhanced capability in terms of tumor growth suppression as compared to the MOF@DOX group, which can be attributed to drug localization in hydrogel superstructure and sustained release at the tumor site. The presented injectable dynamic MOF-based hydrogel is a promising in vivo localized drug delivery system for cancer treatment. Herein, we report the self-healing and shear-thinning of MOF-based drug carrier cross-linked by coordinate bonds for the first time and provide new insights and a facile chemical strategy for designing and fabricating MOF-based biomaterials by using bisphosphonate-zinc interaction.
Bisphosphonate-zinc interaction is a facile chemical strategy to cross-link metal-organic framework (MOF)-based hydrogel. The presented MOF-based hydrogel demonstrates structurally dynamic properties, including smooth injectability, self-healing, and shear-thinning. The developed MOF-based hydrogel possesses pH- and ATP-responsive drug release characteristic and kills cancer cells in vitro efficiently. The dynamic MOF-based hydrogel shows enhanced in vivo anticancer activity as compared to pure MOF particles. Self-healing and shear-thinning of metal-ligand cross-linked MOF-based drug delivery system are reported for the first time, thus providing new insights for the design and fabrication of MOF-based biomaterials.
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