Integrated anti-vascular and immune-chemotherapy for colorectal carcinoma using a pH-responsive polymeric delivery system.

Colorectal carcinoma (CRC) has become one of the most prevalent malignant tumors and exploring a potential therapeutic strategy with diminished drug-associated adverse effects to combat CRC is urgent. Herein, we designed a pH-responsive polymer to efficiently encapsulate a stimulator of interferon genes (STING) agonist (5,6- dimethylxanthenone-4-acetic acid, termed ASA404) and a common clinically used chemotherapeutic agent (1-hexylcarbamoyl-5-fluorouracil, termed HCFU). Investigations in vitro demonstrated that polymer encapsulation endowed the system with a pH-dependent disassembly behavior (pHt 6.37), which preferentially selected cancerous cells with a favorable dose reduction (dose reduction index (DRI) of HCFU was 4.09). Moreover, the growth of CRC in tumor-bearing mice was effectively suppressed, with tumor suppression rates up to 94.74%, and a combination index (CI) value of less than one (CI = 0.41 for CT26 cell lines), indicating a significant synergistic therapeutic effect. Histological analysis of the tumor micro-vessel density and enzyme-linked immunosorbent assay (ELISA) tests indicated that the system increased TNF-α and IFN-ß levels in serum. Therefore, this research introduces a pH-responsive polymer-based theranostic platform with great potential for immune-chemotherapeutic and anti-vascular combination therapy of CRC.

Prognostic value of right ventricular free wall strain in patients with sepsis.

Background: Right ventricular systolic dysfunction (RVSD) in patients with sepsis is an area of growing interest, but its prognostic significance remains unclear and additional tools are needed to improve our understanding. Right ventricular free wall strain (RV-FWS) is a relatively new parameter to assess RV function. This study aimed to investigate the potential correlation between impaired RV-FWS and prognostic outcomes in patients with sepsis. Methods: We prospectively assessed right ventricular function in patients with sepsis within the initial 24 h of their hospital admission. RV-FWS, right ventricular global strain (RV-GS), fractional area change (FAC), and tricuspid annular plane systolic excursion (TAPSE) were examined. RVSD was defined as impaired RV-FWS. Moreover, the association between RVSD and 30-day mortality rate was assessed. Results: This study included 89 patients. Among them, 27 (30.3%) succumbed to their illness within 30 days. The nonsurviving patients demonstrated significantly lower absolute RV-FWS (-19.7% ± 2.4% vs. -21.1% ± 2.1%, P = 0.008) and RV-GS (-17.7% ± 1.2% vs. -18.4% ± 1.4%, P = 0.032) values than the surviving patients. However, TAPSE and FAC values were not significantly different between the two groups. The optimal cutoff values for RV-FWS, RV-GS, FAC, and TAPSE were -19.0%, -17.9%, 36.5%, and 1.55 cm, respectively. Kaplan-Meier survival curves revealed that patients with impaired RV-FWS and RV-GS demonstrated lower 30-day survival rates, and the predictive performance of RV-FWS (hazard ratio [HR]: 3.97, 95% confidence interval [CI]: 1.85-8.51, P < 0.001) was slightly higher than FAC and TAPSE. However, multivariable Cox regression analysis revealed no association between impaired RV-FWS and mortality outcomes (HR: 1.85, 95% CI: 0.56-6.14, P = 0.316). Conclusions: Impaired RV-FWS is not associated with short-term mortality outcomes, and RV strain imaging is of limited value in assessing the prognosis of sepsis.

Extracellular-vesicle-packaged S100A11 from osteosarcoma cells mediates lung premetastatic niche formation by recruiting gMDSCs.

The premetastatic niche (PMN) contributes to lung-specific metastatic tropism in osteosarcoma. However, the crosstalk between primary tumor cells and lung stromal cells is not clearly defined. Here, we dissect the composition of immune cells in the lung PMN and identify granulocytic myeloid-derived suppressor cell (gMDSC) infiltration as positively associated with immunosuppressive PMN formation and tumor cell colonization. Osteosarcoma-cell-derived extracellular vesicles (EVs) activate lung interstitial macrophages to initiate the influx of gMDSCs via secretion of the chemokine CXCL2. Proteomic profiling of EVs reveals that EV-packaged S100A11 stimulates the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway in macrophages by interacting with USP9X. High level of S100A11 expression or circulating gMDSCs correlates with the presentation of lung metastasis and poor prognosis in osteosarcoma patients. In summary, we identify a key role of tumor-derived EVs in lung PMN formation, providing potential strategies for monitoring or preventing lung metastasis in osteosarcoma.

Osteosarcoma Cells Secrete CXCL14 That Activates Integrin α11ß1 on Fibroblasts to Form a Lung Metastatic Niche.

Cooperation between primary malignant cells and stromal cells can mediate the establishment of lung metastatic niches. Here, we characterized the landscape of cell populations in the tumor microenvironment in treatment-naïve osteosarcoma using single-cell RNA sequencing and identified a stem cell-like cluster with tumor cell-initiating properties and prometastatic traits. CXCL14 was specifically enriched in the stem cell-like cluster and was also significantly upregulated in lung metastases compared with primary tumors. CXCL14 induced stromal reprogramming and evoked a malignant phenotype in fibroblasts to form a supportive lung metastatic niche. Binding of CXCL14 to heterodimeric integrin α11ß1 on fibroblasts activated actomyosin contractility and matrix remodeling properties. CXCL14-stimulated fibroblasts produced TGFß and increased osteosarcoma invasion and migration. mAbs targeting the CXCL14-integrin α11ß1 axis inhibited fibroblast TGFß production, enhanced CD8+ T cell-mediated antitumor immunity, and suppressed osteosarcoma lung metastasis. Taken together, these findings identify cross-talk between osteosarcoma cells and fibroblasts that promotes metastasis and demonstrate that targeting the CXCL14-integrin α11ß1 axis is a potential strategy to inhibit osteosarcoma lung metastasis. SIGNIFICANCE: Cooperation between stem-like osteosarcoma cells and fibroblasts mediated by a CXCL14-integrin α11ß1 axis creates a tumor-supportive lung metastatic niche and represents a therapeutic target to suppress osteosarcoma metastasis.

Mass Spectrometry-Based Proteomics Identifies Serpin B9 as a Key Protein in Promoting Bone Metastases in Lung Cancer.

Bone metastasis (BM) is one of the most common complications of advanced cancer. Immunotherapy for bone metastasis of lung cancer (LCBM) is not so promising and the immune mechanisms are still unknown. Here, we utilized a model of BM by injecting cancer cells through caudal artery (CA) to screen out a highly bone metastatic derivative (LLC1-BM3) from a murine lung cancer cell line LLC1. Mass spectrometry-based proteomics was performed in LLC1-parental and LLC1-BM3 cells. Combining with prognostic survival information from patients with lung cancer, we identified serpin B9 (SB9) as a key factor in BM. Molecular characterization showed that SB9 overexpression was associated with poor prognosis and high bone metastatic burden in lung cancer. Moreover, SB9 could increase the ability of lung cancer cells to metastasize to the bone. The mechanistic studies revealed that tumor-derived SB9 promoted BM through an immune cell-dependent way by inactivating granzyme B, manifesting with the decreased infiltration of cytotoxic T cells and increased expression level of exhausted markers. A specific SB9-targeting inhibitor [1,3-benzoxazole-6-carboxylic acid (BTCA)] significantly suppressed LCBM in the CA mouse model. This study reveals that SB9 may serve as a therapeutic target and potential prognostic marker for patients with LCBM. IMPLICATIONS: SB9 as a therapeutic target for LCBM.

Extracellular vesicles released by cancer-associated fibroblast-induced myeloid-derived suppressor cells inhibit T-cell function.

Myeloid cells are known to play a crucial role in creating a tumor-promoting and immune suppressive microenvironment. Our previous study demonstrated that primary human monocytes can be polarized into immunosuppressive myeloid-derived suppressor cells (MDSCs) by cancer-associated fibroblasts (CAFs) in a 3D co-culture system. However, the molecular mechanisms underlying the immunosuppressive function of MDSCs, especially CAF-induced MDSCs, remain poorly understood. Using mass spectrometry-based proteomics, we compared cell surface protein changes among monocytes, in vitro differentiated CAF-induced MDSCs, M1/M2 macrophages, and dendritic cells, and identified an extracellular vesicle (EV)-mediated secretory phenotype of MDSCs. Functional assays using an MDSC/T-cell co-culture system revealed that blocking EV generation in CAF-induced MDSCs reversed their ability to suppress T-cell proliferation, while EVs isolated from CAF-induced MDSCs directly inhibited T-cell function. Furthermore, we identified fructose bisphosphatase 1 (FBP1) as a cargo protein that is highly enriched in EVs isolated from CAF-induced MDSCs, and pharmacological inhibition of FBP1 partially reversed the suppressive phenotype of MDSCs. Our findings provide valuable insights into the cell surface proteome of different monocyte-derived myeloid subsets and uncover a novel mechanism underlying the interplay between CAFs and myeloid cells in shaping a tumor-permissive microenvironment.

Surgical outcomes and risk factors for surgical complications after en bloc resection following reconstruction with 3D-printed artificial vertebral body for thoracolumbar tumors.

BACKGROUND: The outcomes of patients with tumors of the thoracolumbar spine treated with en bloc resection (EBR) using three-dimensional (3D)-printed endoprostheses are underreported. METHODS: We retrospectively evaluated patients with thoracolumbar tumors who underwent surgery at our institution. Logistic regression analysis was performed to identify the potential risk factors for surgical complications. Nomograms to predict complications were constructed and validated. RESULTS: A total of 53 patients with spinal tumors underwent EBR at our hospital; of these, 2 were lost to follow-up, 45 underwent total en bloc spondylectomy, and 6 were treated with sagittal en bloc spondylectomy. The anterior reconstruction materials included a customized 3D-printed artificial vertebral body (AVB) in 10 cases and an off-the-shelf 3D-printed AVB in 41 cases, and prosthesis mismatch occurred in 2 patients reconstructed with the off-the-shelf 3D-printed AVB. The median follow-up period was 21 months (range, 7-57 months). Three patients experienced local recurrence, and 5 patients died at the final follow-up. A total of 50 perioperative complications were encountered in 29 patients, including 25 major and 25 minor complications. Instrumentation failure occurred in 1 patient, and no prosthesis subsidence was observed. Using a combined surgical approach was a dependent predictor of overall complications, while Karnofsky performance status score, lumbar spine lesion, and intraoperative blood loss ≥ 2000 mL were predictors of major complications. Nomograms for the overall and major complications were constructed using these factors, with C-indices of 0.850 and 0.891, respectively. CONCLUSIONS: EBR is essential for the management of thoracolumbar tumors; however, EBR has a steep learning curve and a high complication rate. A 3D-printed AVB is an effective and feasible reconstruction option for patients treated with EBR.

Attenuating RNA Viruses with Expanded Genetic Codes to Evoke Adjustable Immune Response in PylRS-tRNACUAPyl Transgenic Mice.

Ribonucleic acid (RNA) viruses pose heavy burdens on public-health systems. Synthetic biology holds great potential for artificially controlling their replication, a strategy that could be used to attenuate infectious viruses but is still in the exploratory stage. Herein, we used the genetic-code expansion technique to convert Enterovirus 71 (EV71), a prototypical RNA virus, into a controllable EV71 strain carrying the unnatural amino acid (UAA) Nε-2-azidoethyloxycarbonyl-L-lysine (NAEK), which we termed an EV71-NAEK virus. After NAEK supplementation, EV71-NAEK could recapitulate an authentic NAEK time- and dose-dependent infection in vitro, which could serve as a novel method to manipulate virulent viruses in conventional laboratories. We further validated the prophylactic effect of EV71-NAEK in two mouse models. In susceptible parent mice, vaccination with EV71-NAEK elicited a strong immune response and protected their neonatal offspring from lethal challenges similar to that of commercial vaccines. Meanwhile, in transgenic mice harboring a PylRS-tRNACUAPyl pair, substantial elements of genetic-code expansion technology, EV71-NAEK evoked an adjustable neutralizing-antibody response in a strictly external NAEK dose-dependent manner. These findings suggested that EV71-NAEK could be the basis of a feasible immunization program for populations with different levels of immunity. Moreover, we expanded the strategy to generate controllable coxsackieviruses for conceptual verification. In combination, these results could underlie a competent strategy for attenuating viruses and priming the immune system via artificial control, which might be a promising direction for the development of amenable vaccine candidates and be broadly applied to other RNA viruses.

Cu2+ -Anchored Carbon Nano-Photocatalysts for Visible Water Splitting to Boost Hydrogen Cuproptosis.

Both hydrogen (H2 ) and copper ions (Cu+ ) can be used as anti-cancer treatments. However, the continuous generation of H2 molecules and Cu+ in specific sites of tumors is challenging. Here we anchored Cu2+ on carbon photocatalyst (Cu@CDCN) to allow the continuous generation of H2 and hydrogen peroxide (H2 O2 ) in tumors using the two-electron process of visible water splitting. The photocatalytic process also generated redox-active Cu-carbon centers. Meanwhile, the Cu2+ residues reacted with H2 O2 (the obstacle to the photocatalytic process) to accelerate the two-electron process of water splitting and cuprous ion (Cu+ ) generation, in which the Cu2+ residue promoted a pro-oxidant effect with glutathione through metal-reducing actions. Both H2 and Cu+ induced mitochondrial dysfunction and intracellular redox homeostasis destruction, which enabled hydrogen therapy and cuproptosis to inhibit cancer cell growth and suppress tumor growth. Our research is the first attempt to integrate hydrogen therapy and cuproptosis using metal-enhanced visible solar water splitting in nanomedicine, which may provide a safe and effective cancer treatment.

Hybrid Slime Mold and Arithmetic Optimization Algorithm with Random Center Learning and Restart Mutation.

The slime mold algorithm (SMA) and the arithmetic optimization algorithm (AOA) are two novel meta-heuristic optimization algorithms. Among them, the slime mold algorithm has a strong global search ability. Still, the oscillation effect in the later iteration stage is weak, making it difficult to find the optimal position in complex functions. The arithmetic optimization algorithm utilizes multiplication and division operators for position updates, which have strong randomness and good convergence ability. For the above, this paper integrates the two algorithms and adds a random central solution strategy, a mutation strategy, and a restart strategy. A hybrid slime mold and arithmetic optimization algorithm with random center learning and restart mutation (RCLSMAOA) is proposed. The improved algorithm retains the position update formula of the slime mold algorithm in the global exploration section. It replaces the convergence stage of the slime mold algorithm with the multiplication and division algorithm in the local exploitation stage. At the same time, the stochastic center learning strategy is adopted to improve the global search efficiency and the diversity of the algorithm population. In addition, the restart strategy and mutation strategy are also used to improve the convergence accuracy of the algorithm and enhance the later optimization ability. In comparison experiments, different kinds of test functions are used to test the specific performance of the improvement algorithm. We determine the final performance of the algorithm by analyzing experimental data and convergence images, using the Wilcoxon rank sum test and Friedman test. The experimental results show that the improvement algorithm, which combines the slime mold algorithm and arithmetic optimization algorithm, is effective. Finally, the specific performance of the improvement algorithm on practical engineering problems was evaluated.

Ca-DEX biomineralization-inducing nuts reverse oxidative stress and bone loss in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common autoimmune disease, and the inflammatory response during its development can lead to joint cartilage and bone damage up to disability. Dexamethasone (DEX) can effectively alleviate the inflammatory response in RA, but the severe adverse effects that occur after its long-term administration limit its clinical development. Herein, we propose a Ca-DEX biomineralization-inducing nut (CaCO3-DEX) with controlled release properties for mitigating the toxic side effects of DEX in RA treatment, especially the damage to cartilage and bone. CaCO3-DEX releases the drug and Ca2+ preferentially in an inflammatory environment. Both in vitro and in vivo studies demonstrate that CaCO3-DEX significantly reduces the secretion of pro-inflammatory factors and inhibits ROS production in vitro, as well as demonstrates superior pro-biomineralization and osteogenic differentiation potential. In the collagen-induced rheumatoid arthritis model (CIA model), CaCO3-DEX significantly reduces the clinical score of arthritis in mice, and the imaging results show a noticeable relief of edema and bone erosion in CIA model mice treated with CaCO3-DEX, while inflammatory factors at the injury areas are significantly reduced, which provides favorable protection to cartilage and bone.

An improved multi-strategy beluga whale optimization for global optimization problems.

This paper presents an improved beluga whale optimization (IBWO) algorithm, which is mainly used to solve global optimization problems and engineering problems. This improvement is proposed to solve the imbalance between exploration and exploitation and to solve the problem of insufficient convergence accuracy and speed of beluga whale optimization (BWO). In IBWO, we use a new group action strategy (GAS), which replaces the exploration phase in BWO. It was inspired by the group hunting behavior of beluga whales in nature. The GAS keeps individual belugas whales together, allowing them to hide together from the threat posed by their natural enemy, the tiger shark. It also enables the exchange of location information between individual belugas whales to enhance the balance between local and global lookups. On this basis, the dynamic pinhole imaging strategy (DPIS) and quadratic interpolation strategy (QIS) are added to improve the global optimization ability and search rate of IBWO and maintain diversity. In a comparison experiment, the performance of the optimization algorithm (IBWO) was tested by using CEC2017 and CEC2020 benchmark functions of different dimensions. Performance was analyzed by observing experimental data, convergence curves, and box graphs, and the results were tested using the Wilcoxon rank sum test. The results show that IBWO has good optimization performance and robustness. Finally, the applicability of IBWO to practical engineering problems is verified by five engineering problems.

Mumia quercus sp. nov., isolated from the root of Quercus variabilis.

A novel endophytic actinomycete, designated strain NEAU-365T, was isolated from the root of Quercus variabilis collected from Nanjing, Jiangsu, PR China. Comparative 16S rRNA gene sequencing showed that strain NEAU-365T belonged to the genus Mumia but clearly differs from the currently recognized species Mumia zhuanghuii Z350T (99.31 %), Mumia xiangluensis NEAU-KD1T (98.82 %) and Mumia flava MUSC 201T (97.78 %). Phylogenetic tree analysis revealed that strain NEAU-365T clustered with the type strains of the genus Mumia. The genome size was 4.1 Mbp with a DNA G+C content of 71.2 mol%. Digital DNA-DNA hybridization and average nucleotide identity values between the genome sequence of strain NEAU-365T and those of M. zhuanghuii Z350T(27.5 and 84.0 %), M. xiangluensis NEAU-KD1T(23.4 and 80.9 %) and M. flava MUSC 201T(20.9 and 77.7 %) were below the recommended thresholds for species delineation. Cells were observed to be irregular cocci shaped. The cell wall contained ll-diaminopimelic acid and the whole-cell sugars were galactose and rhamnose. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphoglycolipid and three unidentified phospholipids. The predominant menaquinone was detected as MK-9(H4). The major fatty acids were C16 : 0, C18 : 0, C18 : 1 ω9c and 10-methyl C18 : 0. On the basis of genotypic and phenotypic differences from members of the genus Mumia, a novel species, Mumia quercus sp. nov. is proposed. The type strain is NEAU-365T (=CCTCC AA 2021033T=JCM 35005T).

Sphaerisporangium perillae sp. nov., isolated from the root of Perilla frutescens (Linn.) Britt.

A novel protease-producing actinomycete, designated strain NEAU-ZS1T, was isolated from the root of Perilla frutescens (Linn.) Britt collected from Jiamusi, Heilongjiang, PR China. Comparative 16S rRNA gene sequencing showed that strain NEAU-ZS1T belonged to the genus Sphaerisporangium and was most closely related to 'Sphaerisporangium corydalis' NEAU-YHS15T (99.2%) and Sphaerisporangium cinnabarinum JCM 3291T (99.0%). Phylogenetic tree analysis revealed that strain NEAU-ZS1T formed a monophyletic clade with 'S. corydalis' NEAU-YHS15T. The genome size was 9.3 Mbp with a DNA G+C content of 70.3 mol%. Digital DNA-DNA hybridization, average nucleotide identity and average amino acid identity values between the genome sequence of strain NEAU-ZS1T and those of 'S. corydalis' NEAU-YHS15T (28.6, 83.9 and 79.1 %) and S. cinnabarinum JCM 3291T (18.5, 70.6 and 50.2 %) were below the recommended thresholds for species delineation. The strain formed spherical spore vesicles produced on the aerial hyphae. The cell wall contained meso-diaminopimelic acid and the whole-cell sugars were glucose and madurose. The polar lipids consisted of diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine, phosphatidylinositol, an unidentified phospholipid and an unidentified glycolipid. The menaquinones were MK-9(H4), MK-9(H6) and MK-9(H2). The major fatty acids were iso-C16 : 0, C16 : 1 ω5c, 10-methy C17 : 0 and C17 : 1 ω7c. On the basis of the results of a polyphasic taxonomic study, it is concluded that strain NEAU-ZS1T represents a novel species of the genus Sphaerisporangium, for which the name Sphaerisporangium perillae sp. nov. is proposed. The type strain is NEAU-ZS1T (=CCTCC AA 2021019T= JCM 35655T).

Screening of core genes and prediction of ceRNA regulation mechanism of circRNAs in nasopharyngeal carcinoma by bioinformatics analysis.

Background: Nasopharyngeal carcinoma (NPC) represents a highly aggressive malignant tumor. Competing endogenous RNAs (ceRNA) regulation is a common regulatory mechanism in tumors. The ceRNA network links the functions between mRNAs and ncRNAs, thus playing an important regulatory role in diseases. This study screened the potential key genes in NPC and predicted regulatory mechanisms using bioinformatics analysis. Methods: The merged microarray data of three NPC-related mRNA expression microarrays from the Gene Expression Omnibus (GEO) database and the expression data of tumor samples or normal samples from the nasopharynx and tonsil in The Cancer Genome Atlas (TCGA) database were both subjected to differential analysis and Weighted Gene Co-expression Network Analysis (WGCNA). The results from two different databases were intersected with WGCNA results to obtain potential regulatory genes in NPC, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. The hub-gene in candidate genes was discerned through Protein-Protein Interaction (PPI) analysis and its upstream regulatory mechanism was predicted by miRwalk and circbank databases. Results: Totally 68 upregulated genes and 96 downregulated genes in NPC were screened through GEO and TCGA. According to WGCNA, the NPC-related modules were screened from GEO and TCGA analysis results, and the genes in the modules were obtained. After the results of differential analysis and WGCNA were intersected, 74 differentially expressed candidate genes associated with NPC were discerned. Finally, fibronectin 1 (FN1) was identified as a hub-gene in NPC. Prediction of upstream regulatory mechanisms of FN1 suggested that FN1 may be regulated by ceRNA mechanisms involving multiple circRNAs, thereby influencing NPC progression through ceRNA regulation. Conclusion: FN1 is identified as a key regulator in NPC development and is likely to be regulated by numerous circRNA-mediated ceRNA mechanisms.

NIR-II-absorbing diimmonium polymer agent achieves excellent photothermal therapy with induction of tumor immunogenic cell death.

Photothermal therapy has shown great promise for cancer treatment and second near-infrared (NIR-II) -absorbing particles could further improve its precision and applicability due to its superior penetration depth and new imaging ability. Herein, high NIR-II-absorbing polymer particles were prepared by using soluble isobutyl-substituted diammonium borates (P-IDI). The P-IDI showed stronger absorption at 1000-1100 nm, which exhibited excellent photostability, strong photoacoustic imaging ability and high photothermal conversion efficiency (34.7%). The investigations in vitro and in vivo demonstrated that the excellent photothermal effect facilitated complete tumor ablation and also triggered immunogenic cell death in activation of the immune response. The high solubility and excellent photothermal conversion ability demonstrated that polymer IDI particles were promising theranostic agents for treatment of tumors with minor side effects.

G-quadruplex-based CRISPR photoswitch for spatiotemporal control of genomic modulation.

CRISPR (clustered regularly interspaced short palindromic repeats) technology holds tremendous promise for gene regulation and editing. However, precise control of CRISPR editing is essential to overcome its uncontrollable reaction process and excessive activity that leads to off-target editing. To overcome this problem, we engineered a photoswitch on G-quadruplex gRNA (GqRNA) for precisely controlled gene editing and expression by embedding dicationic azobenzene derivatives (AZD++). Our results demonstrated that rational design of the G-quadruplex onto crRNA conferred higher stability and sequence recognition specificity than unmodified single guide (sgRNA). Light-induced isomerization of AZD++ quickly transformed the on state of GqRNA, which facilitated rapid activation of ribonucleoprotein activity for genome editing of on-target sites in cells with excellent editing efficiency. In turn, AZD++-GqRNA promptly refolded to an off state to inhibit genomic cleavage, and limited the generation of off-target effects and by-products. Therefore, the proposed strategy of a photo-reversible modality presents a new opportunity for CRISPR-Cas9 modulation to improve its safety and applicability.

Nanosensitizer-mediated unique dynamic therapy tactics for effective inhibition of deep tumors.

X-ray and ultrasound waves are widely employed for diagnostic and therapeutic purposes in clinic. Recently, they have been demonstrated to be ideal excitation sources that activate sensitizers for the dynamic therapy of deep-seated tumors due to their excellent tissue penetration. Here, we focused on the recent progress in five years in the unique dynamic therapy strategies for the effective inhibition of deep tumors that activated by X-ray and ultrasound waves. The concepts, mechanisms, and typical nanosensitizers used as energy transducers are described as well as their applications in oncology. The future developments and potential challenges are also discussed. These unique therapeutic methods are expected to be developed as depth-independent, minimally invasive, and multifunctional strategies for the clinic treatment of various deep malignancies.