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The clinical translation of cellular therapy is hampered by the scarcity of reliable and consistent cell sources. In this study, we developed an exquisite scaffold featuring the hierarchical structure and biofunctions of silkworm cocoons (CryoSiCo), for boosting cell manufacture and cryopreservation. CryoSiCo was constructed by a creative bottom-up fabrication technique integrating electrospinning, in situ surface functionalization and freeze-shaping, generating a 3D cocoon-mimicking fibrous scaffold composed of graphene oxide-incorporated polylactic acid/gelatin inner fiber core and alginate outer fiber shell. CryoSiCo provided rapid and uniform rewarming for cryopreserved cells, and maximally maintained cell viability and proliferation capability, allowing for effective cryopreservation. Importantly, CryoSiCo could cryopreserve stem cell-scaffold constructs with high cell survival and functions, which can be directly implanted to restore tissue defects. Thus, CryoSiCo represents an appealing biomimetic strategy for storing precious cells and tissue engineered constructs, showing a broad application for fundamental research and applied medicine.

Current three-dimensional (3D) cell culture systems mainly rely on static cell culture and lack the ability to thoroughly manage cell intrinsic behaviors and biological characteristics, leading to unsatisfied cell activity. Herein, we have developed photoactive 3D-printed hypertensile metamaterials based dynamic cell culture system (MetaFold) for guiding cell fate. MetaFold exhibited high elasticity and photothermal conversion efficiency due to its metapattern architecture and micro/nanoscale polydopamine coating, allowing for responding to mechanical and light stimulation to construct dynamic culture conditions. In addition, MetaFold possessed excellent cell adhesion capability and could promote cell viability and function under dynamic stimulation, thereby maximizing cell activity. Importantly, MetaFold could improve the differentiation efficacy of stem cells into cardiomyocytes and even their maturation, offering high-quality precious candidates for cell therapy. Therefore, we present a dual stimuli-responsive dynamic culture system, which provides a physiologically realistic environment for cell culture and biological study.

Hydrazine and its derivatives are well-known environmental hazards and biological carcinogens; therefore, there is a great need for a powerful workflow solution for protecting the public from unexpected exposure to toxic contaminants. Recently, functional surface-enhanced Raman scattering (SERS) exhibits enormous benefits in sensing trace biochemical substances due to its fingerprint-like identification of individual molecules, making it an ideal method for detecting and quantifying hydrazine. Herein, for the first time, we integrated the orthogonal chemical reporter strategy with SERS to build an intelligent hydrazine detection platform (orthogonal chemical SERS, ocSERS), in which 4-mercaptobenzaldehyde was incorporated on a nanoimprinted gold nanopillar array, which acted as an orthogonal coupling partner of hydrazine to form Raman active benzaldehyde hydrazone, allowing for sensitively detecting hydrazine with a detection limit of 10

Although small-molecule agonists of stimulator of interferon genes (STING) show significance in activating the immune system, the dynamic process involved in ligands activating STING remains unclear. Herein, we developed a biochemical strategy, integrating computer simulation and a biochemical engineering approach, to reveal the interaction mechanism between STING and 5,6-dimethylxanthenone-4-acetic acid (DMXAA), an agonist that activates the TANK binding kinase 1-interferon regulatory factor 3 signaling pathway. Specifically, inspired by an analysis of the STING-DMXAA crystal structure, we designed and synthesized DMXAA derivatives to investigate the STING-DMXAA binding model. We identified that the carboxyl moiety of DMXAA was a major pharmacophore responsive to STING activation. In particular, the loss of hydrogen bond interaction between the carboxylic acid of DMXAA and the side chain Thr262 of STING led to STING inhibition. DMXAA

The major challenge in oral cancer is lack of state-of-the-art treatment modality that effectively cures cancer while preserving oral functions. Recent insights into tumor metabolic dependency provide therapeutic opportunity for exploring optimal treatment approaches. Herein, a smart responsive "Energy NanoLock" is developed to improve cancer metabolic intervention through simultaneously inhibiting nutrient supply and energy production. NanoLock is a pomegranate-like nanocomplex of cyclicRGD-modified carboxymethyl chitosan (CyclicRC, pI = 6.7) encapsulating indocyanine green and apoptotic peptides functionalized gold nanoparticles (IK-AuNPs), which together form a dual pH- and photo-responsive therapeutic platform. NanoLock exhibits good stability under physiological conditions, but releases small-size CyclicRC and IK-AuNPs in response to tumor acidic microenvironment, leading to deep tumor penetration. CyclicRC targets integrins to inhibit tumor angiogenesis, and consequently blocks tumor nutrient supply. Meanwhile, IK-AuNPs specifically induce apoptotic peptides and photothermal mediated mitochondrial collapse, and consequently inhibits endogenous energy production, thereby facilitating cell death. Importantly, in both xenograft and orthotopic oral cancer models, NanoLock selectively eliminates tumor with little cross-reactivity with normal tissues, especially oral functions, resulting in prolonged survival of mice. Therefore, NanoLock provides a novel metabolic therapy to exploit synergistic inhibition of exogenous nutrient supply and endogenous energy production, which potentially advances oral cancer treatment. This article is protected by copyright. All rights reserved.

Induced pluripotent stem cells (iPSCs) hold promise in revolutionizing medicine; however, their application potential is limited because of low reprogramming efficiency. Mesenchymal-to-epithelial transition (MET) has been proved to involve reprogramming of somatic cells into iPSCs, making it a promising target for enhancing generation of iPSCs. Here, we nanoengineered N-cadherin-blocking peptide ADH-1 with gold nanoparticles, generating a multivalent N-cadherin antagonist (ADH-AuNPs), for improving reprogramming efficiency through driving cell MET. ADH-AuNPs exhibited good biocompatibility and showed higher N-cadherin inhibitory activity than ADH-1 due to multivalency, thereby enhancing cell-state reprogramming toward epithelial lineages. Particularly, ADH-AuNPs improved reprogramming efficiency by more than 7-fold after introduction of four Yamanaka factors. Importantly, ADH-AuNPs generated iPSCs displayed high stemness and pluripotency in vitro and in vivo. Therefore, we provide a cooperative strategy for promoting the iPSC generation efficacy.

Despite the availability of various treatment options, the inherent complexity of tumors significantly impairs therapeutic efficacy. Recently, combination treatments exhibited great anticancer potential due to low cross-resistance and good therapeutic additivity. Herein, a photoactive metal oxide-black phosphorus biomimetic nanocomplex (photophage) is developed for improving the antitumor combination of ferroptosis and photodynamic therapy (PDT). The photophage is composed of M1 macrophage membrane camouflaged MnO

Implantable probes and needles represent multifunctional biomedical platforms by integrating sensing, stimulation, and drug delivery capabilities. Conventional rigid probes often result in inflammatory responses due to large mechanical mismatch with soft biological tissues, whereas soft probes with improved long-term performances are difficult to be inserted deep into the compliant biological tissues. An emerging class of mechanically transformative materials addresses the challenge by embedding a phase-change material of gallium within an elastomeric matrix. These materials exhibit high stiffness under ambient conditions to enable facile insertion and compliant mechanical properties after implantations. The widespread implementation of mechanically transformative materials is primarily hindered by the lack of facile fabrication techniques for delicate gallium features. In this study, we introduce a solution-based approach for scalable fabrication of gallium-based mechanically transformative materials, which exhibit bistable mechanical properties with large modulations in the modulus by five orders of magnitude. In a solution-based coating process, gallium features are created based on a patterned copper film and then encapsulated with elastomers to form mechanically transformative materials. The height profile of the gallium feature is controlled by the two-dimensional design of the copper pattern, which provides access to delicate and complex three-dimensional features as exemplified by mechanically transformative indwelling needles with sharp tips. The practical suitability is demonstrated by the in vivo implementation of the indwelling needles for long-term chemotherapy. The excellent biocompatibility enables applications of mechanically transformative biomedical devices in chronic implantable systems.

Wound healing is a complex process involved in repairing tissue damage and preventing infection. However, there is a lack of appropriate treatment solutions that can simultaneously promote tissue repair and protect againstbacteria, especially antibiotic-resistant bacteria. In this study, we have developed an injectable hydrogel encapsulating acidic fibroblast growth factor (aFGF) and bacteriophage, termed as ABgel, for combating antibiotic-resistant bacteria and enhancing wound regeneration. ABgel is composed of oxidized sodium alginate (OSA), gelatin and hyaluronic acid (HA), and can rapidly form hydrogel with an elastic modulus of 13 kPa, which mimics the skin tissues. In addition, ABgel can effectively load and stabilize bacteriophage and aFGF, allowing for preventing bacterial infections and improving regeneration of damaged dermal tissues. In vitro studies demonstrate that ABgel exhibits enormous antibacterial activity against antibiotic-resistant E. coli and enhanced angiogenetic activity. Importantly, ABgel can promote skin regeneration and prevent bacterial infections in mice, thereby promoting wound healing process. Therefore, ABgel represents a decent bioactive engineered hydrogel dressing with a broad application potential.

Ferroptosis is a type of nonapoptotic cell death and is gradually emerging as an important anticancer treatment. However, its therapeutic efficacy is impaired by low intracellular levels of reactive oxygen species (ROS) and long-chain polyunsaturated fatty acids, significantly limiting its therapeutic potential. Herein, a multimodal strategy to improve ferroptosis is presented, in which a state-of-art engineered erythrocyte, termed as sonodynamic amplified ferroptosis erythrocyte (SAFE), is developed for simultaneously activating ferroptosis and oxygen-riched sonodynamic therapy (SDT). SAFE is composed of internalizing RGD peptide and red blood cell membrane hybrid camouflaged nanocomplex of hemoglobin, perfluorocarbon, ferroptosis activator (dihomo-γ-linolenic acid, DGLA), and sonosensitizer verteporfin. It is identified that SAFE, under ultrasound stimulation, can not only substantially supply oxygen to overcome tumor hypoxia associated therapeutic resistance, but effectively activate ferroptosis through the coeffect of SDT triggered ROS production and DGLA mediated lipid peroxidation. In vivo studies reveal that SAFE selectively accumulates in tumor tissues and induces desirable anticancer effects under mild ultrasound stimulation. Importantly, SAFE can effectively inhibit tumor growth with minimal invasiveness, resulting in a prolonged survival period of mice. Therefore, a multimodal ferroptosis therapy driven by oxygen-riched sonodynamic peroxidation of lipids, significantly advancing synergistic cancer treatment, is presented.

Robust efficiency for cytosolic small interfering RNA (siRNA) delivery is of great importance for effective gene therapy. To significantly improve the cytosolic siRNA delivery, a "one-pot modular assembly" strategy is developed to assemble a triple-play enhanced cytosolic siRNA delivery system via a facile and innocuous copper-free click reaction. Specifically, three modules are prepared including octreotide for receptor-mediated endocytosis, a cell-penetrating peptide (CPP) for cell penetration, and glutamic acid for the charge-reversal property. All three modules with distinct facilitating endocytosis effects are expediently assembled on the surface of the siRNA/liposome complex to fabricate a multifunctional integrated siRNA delivery system (OCA-CC). OCA-CC has been demonstrated to have enhanced cytosolic delivery and superior gene-silencing efficiency in multiple tumor cells due to the combined effects of all the three modules. High levels of survivin-silencing are also achieved by OCA-CC on orthotopic human breast cancer (MCF-7)-bearing mice accompanied by significant tumor inhibition. This research provides a facile strategy to produce safe and tunable siRNA delivery systems for effective gene therapy and to facilitate the development of multifunctional siRNA vectors.

An accurate measurement of sweat glucose is a promising alternative to invasive finger prick blood test, and may provide effective self-monitoring of blood glucose with good patient compliance. Herein, an interrelated catalytic enzyme system has been developed, termed as CataFlower, which is composed of nanoflower MoS2 (peroxidase) decorated with GOx (glucose oxidase) and MnO2 (oxygen generator), and exhibits synergistic oxidative capability for sensitively monitoring sweat glucose. CataFlower can not only generate oxygen in situ to maximize GOx activity, but promote peroxidase-triggered H2O2 oxidation of methylene blue, resulting in sensitive colorimetric detection of glucose. We identify that CataFlower can precisely detect glucose with a detection limit of 10 μM, allowing for measuring glucose levels in different biological samples, such as blood and urine. Particularly, CataFlower is capable of monitoring dynamic changes in sweat glucose with high sensitivity and accuracy during exercise. Therefore, CataFlower provides a stepping stone to eliminate invasive blood tests, significantly improving the diagnosis and management of diabetes mellitus.

Compared with the traditional image classification task, fine-grained image classification has the difficulty of small differences between classes and large differences within classes. In view of this difficulty, attention proposal has been widely used in fine-grained image classification. However, traditional attention proposal has to localize first and then processing. Model needs to run step by step and the attention focusing method is single. This paper proposed a model (MAMDL, Multi-Attention-Multi-Depth-Learning) which combines multiple attention mechanisms and multi network parallel learning. The advantage of MAMDL is that it can first learn end-to-end. Secondly, the multiple attention mechanisms can effectively combine four attention mechanisms to improve the network’s ability to process local features. Finally, this paper focuses on the attention found in the backbone network, Feature extraction from branch convolution neural networks with different depths enhances the classification performance of the model. The experimental results show that MAMDL outperforms mainstream fine-grained image classification methods on the fine-grained image classification dataset CUB-200, Stanford dogs and Stanford cars.

The combined therapy of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and heat shock protein 70-targeting siRNA (siHSP70) has shown an improved anti-tumor effect on TRAIL-resistant tumor. However, vehicles to co-deliver these two biopharmaceuticals are challenging because of the distinct location of their targets on the cell surface and in the cytosol. Here we developed a hierarchically modular assembly formulation (TH-s-RSC) via the copper-free click reaction to co-encapsulate the positively-charged TRAIL and negatively-charged siHSP70 and release them in the extracellular space and cytoplasm. We demonstrate that TH-s-RSC can protect the packaged biopharmaceuticals through its hyaluronic acid shell in vivo, and sequentially release TRAIL in response to extracellular molecular including hyaluronidase (HAase) and matrix metalloproteinase 2 (MMP2), followed by the release of siHSP70 triggered by the reductive conditions in the cytoplasm. We showed that the complementary activity of TRAIL and siHSP70 exhibited superior synergistic anticancer efficacy in both A549 lung cancer xenograft models and 4T1 lung metastatic breast cancer models, compared to either treatment alone. Our strategy provides a promising platform for safe and effective co-delivery and dual-site targeting of biopharmaceuticals in cancer treatment that may be applicable in the future.

Despite multiple treatment options being available, many critical challenges are still ongoing in the treatment of oral squamous cell carcinoma (OSCC). Particularly, the major hurdle is to avoid facial disfigurement and oral function disability during treatment. Herein, nanoengineered mesenchymal stem cells (MSCs) are developed as a supersonosensitizer, named M/LPV/O2 , for improving nondestructive sonodynamic therapy (SDT) against OSCC along with good therapeutic compliance. M/LPV/O2 is composed of an MSCs membrane functionalized liposomal formulation of oxygen-loading perfluorocarbon and sonosensitizer verteporfin (M/LPV/O2 ), which can not only increase circulation and targeting efficacy but also supply oxygen to overcome tumor-hypoxia-associated resistance in SDT, resulting in enhanced therapeutic outcomes in vitro and in vivo. It is identified that M/LPV/O2 effectively stimulates the generation of reactive oxygen species even in hypoxic conditions, and consequently tremendously induces cancer cell death. In addition, M/LPV/O2 displays good tumor accumulation and penetration under ultrasound stimulation, and efficiently induces tumor inhibition and even abrogation, leading to prolonged survival of tumor-bearing mice. Importantly, M/LPV/O2 -based SDT exhibits minimal systemic adverse effects and successfully maintains oral functions with no facial tissue damage. Therefore, these studies provide a promising therapeutic strategy for OSCC, which has a potential to enhance life quality and compliance after treatment.

Drug resistance is a major hindrance in the anticancer treatment, which encourages the development of effective therapeutic strategies. For the first time, MDM2-mediated p53 degradation was identified as a critical factor for developing acquired resistance of doxorubicin (DOX) in HepG2 tumor spheroids, which could be effectively reversed by MDM2 inhibitor MI-773, thereby improving anticancer effects. Therefore, a pH-sensitive liposomal formulation of DOX and MI-773 (LipD/M@CMCS) were developed for recovering p53-mediated DOX resistance in hepatocellular carcinoma. LipD/M@CMCS were composed of cationic liposomes covered with carboxymethyl chitosan (pI = 6.8), and were stable in the physiological condition (pH 7.4), but rapidly converted to cationic liposomes in tumor acidic microenvironment (pH 6.5), endowing them with tumor specificity and enhanced cellular uptake. We showed that LipD/M@CMCS could not only effectively induce cell apoptosis in HepG2 tumor spheroids, but significantly inhibit tumor growth with minimal adverse effects. In summary, selective regulation of MDM2 in cancer cells is a promising strategy to overcome DOX resistance, and may provide a perspective on the management of malignant tumors.

Modulating the vitamin D receptor (VDR) is an effective way to treat for cancer. We previously reported a potent non-secosteroidal VDR modulator (sw-22) with modest anti-tumor activity, which could be due to its undesirable physicochemical and pharmacokinetic properties. In this study, we investigated the structure-activity and structure-property relationships around the 2′-hydroxyl group of sw-22 to improve the physicochemical properties, pharmacokinetic properties and anti-tumor activity. Compounds 19a and 27b, the potent non-secosteroidal VDR modulators, were identified as the most effective molecules in inhibiting the proliferation of three cancer cell lines, particularly breast cancer cells, with a low IC50 via the distribution of cell cycle and induction of apoptosis by stimulating the expression of p21, p27 and Bax. Further investigation revealed that 19a and 27b possessed favorable rat microsomal metabolic stability (2.22 and 2.3 times, respectively, more stable than sw-22), solubility (43.9 and 50.2 times, respectively, more soluble than sw-22) and in vivo pharmacokinetic properties. In addition, 19a and 27b showed excellent in vivo anti-tumor activity without cause hypercalcemia, which is the main side effect of marketed VDR modulators. In summary, the favorable physicochemical properties, pharmacokinetic properties and anti-tumor activity of 19a and 27b highlight their potential therapeutic applications in cancer treatment.

As an economic crop, pepper satisfies people's spicy taste and has medicinal uses worldwide. To gain a better understanding of Capsicum evolution, domestication, and specialization, we present here the genome sequence of the cultivated pepper Zunla-1 (C. annuum L.) and its wild progenitor Chiltepin (C. annuum var. glabriusculum). We estimate that the pepper genome expanded similar to 0.3 Mya (with respect to the genome of other Solanaceae) by a rapid amplification of retrotransposons elements, resulting in a genome comprised of similar to 81% repetitive sequences. Approximately 79% of 3.48-Gb scaffolds containing 34,476 protein-coding genes were anchored to chromosomes by a high-density genetic map. Comparison of cultivated and wild pepper genomes with 20 resequencing accessions revealed molecular footprints of artificial selection, providing us with a list of candidate domestication genes. We also found that dosage compensation effect of tandem duplication genes probably contributed to the pungent diversification in pepper. The Capsicum reference genome provides crucial information for the study of not only the evolution of the pepper genome but also, the Solanaceae family, and it will facilitate the establishment of more effective pepper breeding programs.