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CRISPR-Cas9 gene editing has emerged as a powerful therapeutic technology, but the lack of safe and efficient in vivo delivery systems, especially for tissue-specific vectors, limits its broad clinical applications. Delivery of Cas9 ribonucleoprotein (RNP) owns competitive advantages over other options; however, the large size of RNPs exceeds the loading capacity of currently available delivery vectors. Here, we report a previously unidentified genome editing delivery system, named exosome RNP , in which Cas9 RNPs were loaded into purified exosomes isolated from hepatic stellate cells through electroporation. Exosome RNP facilitated effective cytosolic delivery of RNP in vitro while specifically accumulated in the liver tissue in vivo. Exosome RNP showed vigorous therapeutic potential in acute liver injury, chronic liver fibrosis, and hepatocellular carcinoma mouse models via targeting p53 up-regulated modulator of apoptosis ( PUMA ), cyclin E1 ( CcnE1 ), and K (lysine) acetyltransferase 5 ( KAT5 ), respectively. The developed exosome RNP provides a feasible platform for precise and tissue-specific gene therapies of liver diseases.

RAS genes are the most frequently mutated oncogenes and play critical roles in the development and progression of malignancies. The mutation, isoform (KRAS, HRAS, and NRAS), position, and type of substitution vary depending on the tissue types. Despite decades of developing RAS-targeted therapies, only small subsets of these inhibitors are clinically effective, such as the allele-specific inhibitors against KRAS

Despite the great promise initially demonstrated by photothermal ablation (PTA) therapy, its inability to completely ablate large tumors is problematic, because this has been found to result in residual tumors at ablation margins and bring a relative high rate of subsequent recurrences and metastases. To address this issue, we herein report a smart photothermal nanosystem (PBM) based on FDA-approved Prussian blue (PB) nanoparticles, doped with Mn (III) to suppress the tumor debris left by incomplete ablation. Notably, our study demonstrated that PTA-induced hyperthermia plays a crucial role in initiating the cGAS-STING pathway by generating damaged cytosolic DNA. This PBM nanosystem, which consumes glutathione and continuously releases Mn(II), further amplifies the PTA-induced cGAS-STING pathway in CT26 colon and 4T1 breast tumor models. Moreover, treatment with PBM following PTA boosted the robust immune response in situ and extended to the whole body with a remarkable suppression effect on both local residual and distant tumors. This work, which improves the antitumor efficacy of nonablated areas utilizing hyperthermia-enhanced immune therapy, may therefore provide a promising adjuvant antitumor strategy for the issue of incomplete ablation. STATEMENT OF SIGNIFICANCE: This work discovered, for the first time, that photothermal ablation-induced hyperthermia plays a crucial role in initiating the cGAS-STING pathway. Taking advantage of this finding, we developed a smart photothermal material (PBM) tailored for incomplete tumor ablation. This integrated Mn(III)-doped nanosystem (PBM) demonstrated superior therapeutic benefits due to the thermal ablation process and immune enhancement. As the photothermal ablation-induced cGAS-STING pathway was triggered, the released Mn(III) consumes GSH while continuously transferred to Mn(II), which further amplified STING activation and facilitated a more robust antitumor immunity, thereby remarkably inhibiting both local residual and distant tumors in virtue of the biological changes under thermal ablation.

Multiview video coding (MVC) aims to compress the multiview video through the elimination of video redundancies, where the quality of the reference frame directly affects the compression efficiency. In this paper, we propose a deep virtual reference frame generation method based on a disparity-aware reference frame generation network (DAG-Net) to transform the disparity relationship between different viewpoints and generate a more reliable reference frame. The proposed DAG-Net consists of a multi-level receptive field module, a disparity-aware alignment module, and a fusion reconstruction module. First, a multi-level receptive field module is designed to enlarge the receptive field, and extract the multi-scale deep features of the temporal and inter-view reference frames. Then, a disparity-aware alignment module is proposed to learn the disparity relationship, and perform disparity shift on the inter-view reference frame to align it with the temporal reference frame. Finally, a fusion reconstruction module is utilized to fuse the complementary information and generate a more reliable virtual reference frame. Experiments demonstrate that the proposed reference frame generation method achieves superior performance for multiview video coding.

High-power red lasers (mainly at 639 and 670 nm) based on Pr

Rationale: The synergism of new modalities alongside chemodynamic therapy into common chemotherapy has shown promising potential in clinical applications. This paper reports a tumor microenvironment-responsive nanosystem for chemodynamic/chemical synergistic therapy and magnetic resonance imaging (MRI). Methods: The biodegradable nanosystem is synthesized using a surface-modified chain transfer agent for surface-initiated living radical polymerization of the chemotherapeutic drug. Results: In this nanosystem, named CAMNSN@PSN38, the cycling time and solubility of the chemotherapeutic drug are improved. The nanoparticles delivered to tumor tissues gradually release the chemotherapeutic drug and Mn2+ through glutathione (GSH)-triggered biodegradation in the tumor microenvironment. SN38, the released chemotherapeutic drug, not only shows excellent chemical therapy effects but also improves the generation of H2O2. Furthermore, with the Fenton-like agent Mn2+, the generation of reactive oxygen species (ROS) is improved markedly. Finally, CAMNSN@PSN38 shows excellent inhibition of tumor growth in three colorectal cancer tumor models, with an improved accumulation of ROS and controlled release of SN38. Conclusions: The CAMNSN@PSN38-mediated chemodynamic/chemical synergistic therapy provides a promising paradigm for the treatment and MRI-guided therapy of colorectal cancer.

Nanotechnology has a remarkable impact on the preclinical development of future medicines. However, the complicated preparation and systemic toxicity to living systems prevent them from translation to clinical applications. In the present report, we developed a polyepicatechin-based on/off switchable ultra-sensitive magnetic resonance imaging (MRI) visible theranostic nanoparticle (PEMN) for image-guided photothermal therapy (PTT) using our strategy of integrating polymerization and biomineralization into the protein template. We have exploited natural polyphenols as the near infra-red (NIR) switchable photothermal source and MnO2 for the MRI-guided theranostics. PEMN demonstrates excellent MRI contrast ability with a longitudinal relaxivity value up to 30.01 mM-1 s-1. PEMN has shown great tumor inhibition on orthotopic breast tumors and the treatment could be made switchable with an on/off interchangeable mode as needed. PEMN was found to be excretable mainly through the kidneys, avoiding potential systemic toxicity. Thus, PEMN could be extremely useful for developing on-demand therapeutics via'see it and treat it' means with distinguished MRI capability and on/off switchable photothermal properties.

Nanotheranostics (combined diagnosis and therapy) is emerging as an integral part of future therapeutic strategies. However, the development and fabrication of a nanotheranostic module involves multistep processes and always faces formulation challenges. The complexity involved in its multi-step formulations hinders its reproducible industrial production and clinical translation. Therefore, a facile synthesis of multifunctional nanotheranostics is critical to its translational success. In this report, we have developed a one-pot facile strategy to prepare a MRI-visible photothermal theranostic switchable module (T-SWITCH). These nanoparticles are synthesized through polymerization of levodopa together with the reduction of KMnO4 in the presence of silk sericin for the formation of manganese dioxide particles within the T-SWITCH. The synthesized T-SWITCH showed a uniform size distribution of around 95.77 nm and high longitudinal relaxivity coefficient (r1) of up to 61.94 mM-1 s-1. The reported r1 of the T-SWITCH is exceedingly higher than that of any other previously reported manganese-based contrast agents with first-rate in vitro and in vivo contrast enhancement capability. The T-SWITCH can be activated to switch its therapeutic mode using near-infrared (NIR) light. It exhibited strong excitable absorption in the safer and biological NIR window between 650 and 900 nm. We have validated the significant anti-cancer therapeutic efficacy of T-SWITCH both in vitro and in vivo through switchable photothermal therapy.

Aiming at the lack of regional overall planning and reasonable construction schemes in the development of the Ubiquitous Power Internet of Things, based on the form and planning boundaries of the current development, this paper proposes a planning about "aiming at one goal, planning six areas and creating eighteen key projects". About the 18 key projects, the overall technical architecture are about six major areas, including "application innovation, platform construction, communication network, information perception, security protection, business development". And the planning implementation path is "Energy business datamation, Energy data servitization, Energy service valuation, Energy value ecological cultivation, Energy ecological business updation ". They provide technical framework and planning proposal suggestions for regional Ubiquitous Power Internet of Things planning and construction.

Huiyang Wang,1,* Siqi Wang,2,* Xisong Zhu,3 Wenxiu Ding,4 Tianlun Shen,2 Hongjie Fan,1 Yanhua Zhang,5 Lijun Peng,6 Hong Yuan,6 Xiangrui Liu,7 Jun Ling,2 Jihong Sun1 1Department of Radiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China; 2MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, People’s Republic of China; 3Department of Radiology, Quzhou Central Hospital Affiliated to Zhejiang Chinese Medical University, Quzhou, 324002, People’s Republic of China; 4Department of Ultrasound Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, People’s Republic of China; 5Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China; 6College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310030, People’s Republic of China; 7Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jihong Sun, Department of Radiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China, Tel +13857176538, Fax +571-86006762, Email sunjihong@zju.edu.cn Jun Ling, MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, People’s Republic of China, Tel +13645717301, Fax +571-87953739, Email lingjun@zju.edu.cnPurpose: To develop an iron-based solid lipid nanoparticle (SLN) absorbable by the intestinal wall and assess the differential diagnostic value of intestinal lesions in magnetic resonance imaging (MRI).Methods: SLNs were prepared with the simultaneous loading of trivalent Fe ions (Fe3+), levodopa methyl ester (DM), and fluorescein isothiocyanate (FITC). We evaluated the particle size, loading rate, encapsulation efficiency, and cytotoxicity of SLNs. The T1 contrast effects of the FeDM-FITC-SLNs and gadolinium-based contrast agent (GBCA) were compared in different mouse models: acute ulcerative colitis (AUC), chronic ulcerative colitis (CUC), colon adenocarcinoma (COAD), and normal control. MRI was performed in the same mouse with intravenous injection of GBCA on day 1 and enema of FeDM-FITC-SLNs on day 2. The signal-to-noise ratios (SNRs) were compared using one-way analysis of variance. Tissues were then collected for histology.Results: The average particle size of FeDM-FITC-SLN was 220 nm. The mean FeDM loading rate was 94.3%, and the encapsulation efficiency was 60.3%. The relaxivity was 4.02 mM− 1·s− 1. After enema with FeDM-FITC-SLNs, MRI showed the following contrast enhancement duration: AUC = COAD > normal > CUC. Confocal fluorescence microscopy confirmed that FeDM-FITC-SLNs were mainly distributed in the intestinal mucosa and tumor capsule.Conclusion: Iron-based SLNs are promising alternatives for contrast enhancement at T1-weighted MRI and will help in the differential diagnosis of intestinal bowel diseases (IBDs).Keywords: solid lipid nanoparticles, magnetic resonance imaging, contrast agent, ferric iron, intestinal bowel diseases

Cholesterol contributes to the structural basis of biological membranes and functions as a signaling molecule, whose dysregulation has been associated with various human diseases. Here, we report that the long non-coding RNA (lncRNA) SNHG6 increases progression from non-alcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC) by modulating cholesterol-induced mTORC1 activation. Mechanistically, cholesterol binds ER-anchored FAF2 protein to promote the formation of a SNHG6-FAF2-mTOR complex. As a putative cholesterol effector, SNHG6 enhances cholesterol-dependent mTORC1 lysosomal recruitment and activation via enhancing FAF2-mTOR interaction at ER-lysosome contacts, thereby coordinating mTORC1 kinase cascade activation with cellular cholesterol biosynthesis in a self-amplified cycle to accelerate cholesterol-driven NAFLD-HCC development. Notably, loss of SNHG6 inhibits mTORC1 signaling and impairs growth of patient-derived xenograft liver cancer tumors, identifyifng SNHG6 as a potential target for liver cancer treatment. Together, our findings illustrate the crucial role of organelle-associated lncRNA in organelle communication, nutrient sensing, and kinase cascades.

Effective combination therapies are urgently needed to treat triple-negative breast cancer (TNBC), which is insensitive to the existing treatment regimens. However, the synergistic potency of traditional small-molecule combinations is limited in TNBC mainly due to mismatched molar ratios, inconsistent pharmacokinetics, and intratumoral accumulation of individual drugs. Here, we find that the autophagy inhibitor hydroxychloroquine (HCQ) and the topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN38) exhibit synergistic effects when the molar ratio reaches 5:1. We further develop a glutathione-responsive self-assembled combination nanoparticle (Combo NP) to integrate individual HCQ and SN38 polymeric prodrugs at the optimized ratio. In TNBC cells treated with Combo NP, HCQ-mediated autophagy blockage significantly enhances the DNA damage and apoptotic effect of SN38, manifesting synergistically cytotoxic effects of Combo NP. In vivo evaluations show that Combo NP maintains the molar ratio of HCQ to SN38 within the synergistic range in mouse blood circulation and intratumoral tissues. More importantly, Combo NP elicits superior therapeutic benefit in metastatic TNBC models, compared to free drug combination as well as single drug nanoparticles. Taken together, our engineered nanosystem highlights a nanoprodrug-based chemosensitizing approach for improving the therapeutic response to TNBC, addressing the major challenges of the current combination therapy.

Background The prognosis of patients with advanced gastric cancer (GC) remains unsatisfactory owing to distant metastasis and resistance to concurrent systemic therapy. Cancer-associated fibroblasts (CAFs), as essential participators in the tumor microenvironment (TME), play a vital role in tumor progression. Thus, CAFs-targeting therapy is appealing for remodeling TME and sensitizing GC to conventional systemic therapy. Methods Amphiphilic SN38 prodrug polymeric micelles (PSN38) and encapsulated the hydrophobic esterase-responsive prodrug of Triptolide (TPL), triptolide-naphthalene sulfonamide (TPL-nsa), were synthesized to form PSN38@TPL-nsa nanoparticles. Then, CAFs were isolated from fresh GC tissues and immortalized. TPL at low dose concentration was used to investigate its effect on CAFs and CAFs-induced GC cells proliferation and migration. The synergistic mechanism and antitumor efficiency of SN38 and TPL co-delivery nanoparticle were investigated both in vitro and in vivo. Results Fibroblast activation protein (FAP), a marker of CAFs, was highly expressed in GC tissues and indicated poorer prognosis. TPL significantly reduced CAFs activity and inhibited CAFs-induced proliferation, migration and chemotherapy resistance of GC cells. In addition, TPL sensitized GC cells to SN38 treatment through attenuated NF-κB activation in both CAFs and GC cells. PSN38@TPL-nsa treatment reduced the expression of collagen, FAP, and α-smooth muscle actin (α-SMA) in tumors. Potent inhibition of primary tumor growth and vigorous anti-metastasis effect were observed after systemic administration of PSN38@TPL-nsa to CAFs-rich peritoneal disseminated tumor and patient-derived xenograft (PDX) model of GC. Conclusion TPL suppressed CAFs activity and CAFs-induced cell proliferation, migration and chemotherapy resistance to SN38 of GC. CAFs-targeted TPL and SN38 co-delivery nanoparticles exhibited potent efficacy of antitumor and reshaping TME, which was a promising strategy to treat advanced GC. Graphical Abstract

Peptide dendrimers have a broad application in biomedical science due to their biocompatibility, diversity, and multifunctionality, but the precision synthesis of high-molecule weight peptide dendrimers remains challenging. We here report the facile and liquid-phase synthesis of molecular level precision and amino-acid built-in polylysine (PLL) dendrimers with molecular weights as high as ∼60 kDa. Three types of polyhedral oligosilsesquioxane (POSS)-cored PLL dendrimers with phenylalanine, tyrosine, or histidine as building blocks were synthesized. The precise structures of the dendrimers were confirmed by MALDI-TOF MS, GPC, and 1H NMR spectroscopy. The interior functionalized peptide dendrimers improved the encapsulation capability of SN38 and sustained the release profiles. Enhanced molecular interactions between the peptide dendrimers and drugs were explored by both NMR experiments and computer simulations. The peptide dendrimer/SN38 formulations showed potent antitumor activity against multiple cancer cell lines. We believe that this strategy can be applied to the synthesis of tailor-made functional peptide dendrimers for drug-specific delivery and other diverse biomedical applications.

Polymeric nanocapsules hold considerable applications in cancer drug delivery, but the synthesis of well-defined nanocapsules with a tunable drug release property remains a significant challenge in fabrication. Herein, we demonstrate a supramolecular complexation strategy to assemble small molecular platinum (Pt) compounds into well-defined nanocapsules with high drug loading, acidity-sensitivity, and tunable Pt releasing profile. The design utilizes poly(ethylene glycol)-dendritic polylysine-G4/amides to complex with Pt compounds, forming stable nanocapsules with diameters approximately ∼20 nm and membrane thickness around several nanometers. The stability, drug content, and release profiles are tunable by tailoring the dendritic structure. The designated polymer-Pt nanocapsules, PEG-G4/MSA-Pt, showed sustained blood retention, preferential tumor accumulation, enhanced cellular uptake, lysosomal drug release, and nuclear delivery capability. PEG-G4/MSA-Pt showed enhanced antitumor efficacy compared to free cisplatin and other nanocapsules, which stopped the progression of both A549 cell xenografts and patient-derived xenografts (PDXs) of hepatocellular carcinoma on a mice tumor model. Thus, we believe this strategy is promising for developing Pt-based nanomedicine for cancer drug delivery.