The mechanisms, regulations, and functions of histone lysine crotonylation.

Histone lysine crotonylation (Kcr) is a new acylation modification first discovered in 2011, which has important biological significance for gene expression, cell development, and disease treatment. In the past over ten years, numerous signs of progress have been made in the research on the biochemistry of Kcr modification, especially a series of Kcr modification-related "reader", "eraser", and "writer" enzyme systems are identified. The physiological function of crotonylation and its correlation with development, heredity, and spermatogenesis have been paid more and more attention. However, the development of disease is usually associated with abnormal Kcr modification. In this review, we summarized the identification of crotonylation modification, Kcr-related enzyme system, biological functions, and diseases caused by abnormal Kcr. This knowledge supplies a theoretical basis for further exploring the function of crotonylation in the future.

A Double-ligand Chelating Strategy to Iron Complex Anolytes with Ultrahigh Cyclability for Aqueous Iron Flow Batteries.

Aqueous all-iron flow batteries (AIFBs) are attractive for large-scale and long-term energy storage due to their extremely low cost and safety features. To accelerate commercial application, a long cyclable and reversible iron anolyte is expected to address the critical barriers, namely iron dendrite growth and hydrogen evolution reaction (HER). Herein, we report a robust iron complex with triethanolamine (TEA) and 2-methylimidazole (MM) double ligands. By introducing two ligands into one iron center, the binding energy of the complex increases, making it more stable in the charge-discharge reactions. The Fe(TEA)MM complex achieves reversible and stable redox between Fe3+ and Fe2+ , without metallic iron growth and HER. AIFBs based on this anolyte perform a high energy efficiency of 80.5 % at 80 mA cm-2 and exhibit a record durability among reported AIFBs. The efficiency and capacity retain nearly 100 % after 1,400 cycles. The capital cost of this AIFB is $ 33.2 kWh-1 (e.g., 20 h duration), cheaper than Li-ion battery and vanadium flow battery. This double-ligand chelating strategy not only solves the current problems faced by AIFBs, but also provides an insight for further improving the cycling stability of other flow batteries.

Circular RNA FEACR inhibits ferroptosis and alleviates myocardial ischemia/reperfusion injury by interacting with NAMPT.

BACKGROUND: Emerging research has reported that circular RNAs (circRNAs) play important roles in cardiac cell death after myocardial ischemia and reperfusion (I/R). Ferroptosis, a new form of cell death discovered in recent years, has been proven to participate in the regulation of myocardial I/R. This study used circRNA sequencing to explore the key circRNA in the regulation of cardiac ferroptosis after I/R and study the mechanisms of potential circRNA function. METHODS: We performed circRNA sequencing to explore circRNAs differentially expressed after myocardial I/R. We used quantitative polymerase chain reactions to determine the circRNA expression in different tissues and detect the circRNA subcellular localization in the cardiomyocyte. Gain- and loss-of-function experiments were aimed to examine the function of circRNAs in cardiomyocyte ferroptosis and cardiac tissue damage after myocardial I/R. RNA pull-down was applied to explore proteins interacting with circRNA. RESULTS: Here, we identified a ferroptosis-associated circRNA (FEACR) that has an underlying regulatory role in cardiomyocyte ferroptosis. FEACR overexpression suppressed I/R-induced myocardial infarction and ameliorated cardiac function. FEACR inhibition induces ferroptosis in cardiomyocytes and FEACR overexpression inhibits hypoxia and reoxygenation-induced ferroptosis. Mechanistically, FEACR directly bound to nicotinamide phosphoribosyltransferase (NAMPT) and enhanced the protein stability of NAMPT, which increased NAMPT-dependent Sirtuin1 (Sirt1) expression, which promoted the transcriptional activity of forkhead box protein O1 (FOXO1) by reducing FOXO1 acetylation levels. FOXO1 further upregulated the transcription of ferritin heavy chain 1 (Fth1), a ferroptosis suppressor, which resulted in the inhibition of cardiomyocyte ferroptosis. CONCLUSIONS: Our finding reveals that the circRNA FEACR-mediated NAMPT-Sirt1-FOXO1-FTH1 signaling axis participates in the regulation of cardiomyocyte ferroptosis and protects the heart function against I/R injury. Thus, FEACR and its downstream factors could be novel targets for alleviating ferroptosis-related myocardial injury in ischemic heart diseases.

Spontaneous Threshold Lowering Neuron using Second-Order Diffusive Memristor for Self-Adaptive Spatial Attention.

Intrinsic plasticity of neurons, such as spontaneous threshold lowering (STL) to modulate neuronal excitability, is key to spatial attention of biological neural systems. In-memory computing with emerging memristors is expected to solve the memory bottleneck of the von Neumann architecture commonly used in conventional digital computers and is deemed a promising solution to this bioinspired computing paradigm. Nonetheless, conventional memristors are incapable of implementing the STL plasticity of neurons due to their first-order dynamics. Here, a second-order memristor is experimentally demonstrated using yttria-stabilized zirconia with Ag doping (YSZ:Ag) that exhibits STL functionality. The physical origin of the second-order dynamics, i.e., the size evolution of Ag nanoclusters, is uncovered through transmission electron microscopy (TEM), which is leveraged to model the STL neuron. STL-based spatial attention in a spiking convolutional neural network (SCNN) is demonstrated, improving the accuracy of a multiobject detection task from 70% (20%) to 90% (80%) for the object within (outside) the area receiving attention. This second-order memristor with intrinsic STL dynamics paves the way for future machine intelligence, enabling high-efficiency, compact footprint, and hardware-encoded plasticity.

Electronic/Optoelectronic Memory Device Enabled by Tellurium-based 2D van der Waals Heterostructure for in-Sensor Reservoir Computing at the Optical Communication Band.

Although 2D materials are widely explored for data storage and neuromorphic computing, the construction of 2D material-based memory devices with optoelectronic responsivity in the short-wave infrared (SWIR) region for in-sensor reservoir computing (RC) at the optical communication band still remains a big challenge. In this work, an electronic/optoelectronic memory device enabled by tellurium-based 2D van der Waals (vdW) heterostructure is reported, where the ferroelectric CuInP2 S6 and tellurium channel endow this device with both the long-term potentiation/depression by voltage pulses and short-term potentiation by 1550 nm laser pulses (a typical wavelength in the conventional fiber optical communication band). Leveraging the rich dynamics, a fully memristive in-sensor RC system that can simultaneously sense, decode, and learn messages transmitted by optical fibers is demonstrated. The reported 2D vdW heterostructure-based memory featuring both the long-term and short-term memory behaviors using electrical and optical pulses in SWIR region has not only complemented the wide spectrum of applications of 2D materials family in electronics/optoelectronics but also paves the way for future smart signal processing systems at the edge.

Cre-loxP-mediated genetic lineage tracing: Unraveling cell fate and origin in the developing heart.

The Cre-loxP-mediated genetic lineage tracing system is essential for constructing the fate mapping of single-cell progeny or cell populations. Understanding the structural hierarchy of cardiac progenitor cells facilitates unraveling cell fate and origin issues in cardiac development. Several prospective Cre-loxP-based lineage-tracing systems have been used to analyze precisely the fate determination and developmental characteristics of endocardial cells (ECs), epicardial cells, and cardiomyocytes. Therefore, emerging lineage-tracing techniques advance the study of cardiovascular-related cellular plasticity. In this review, we illustrate the principles and methods of the emerging Cre-loxP-based genetic lineage tracing technology for trajectory monitoring of distinct cell lineages in the heart. The comprehensive demonstration of the differentiation process of single-cell progeny using genetic lineage tracing technology has made outstanding contributions to cardiac development and homeostasis, providing new therapeutic strategies for tissue regeneration in congenital and cardiovascular diseases (CVDs).

LncCat: An ORF attention model to identify LncRNA based on ensemble learning strategy and fused sequence information.

Background: Long non-coding RNA (lncRNA) is one of the most essential forms of transcripts, playing crucial regulatory roles in the development of cancers and diseases without protein-coding ability. It was assumed that short ORFs (sORFs) in lncRNA were weak to translate proteins. However, recent research has shown that sORFs can encode peptides, which increases the difficulty to identify lncRNA. Therefore, identifying lncRNAs with sORFs facilitates finding novel regulatory factors. Results: In this paper, we propose LncCat for identifying lncRNA based on category boosting (CatBoost) and ORF-attention features. LncCat combines five types of features to encode transcript sequences and employs CatBoost to build a prediction model. In addition, the visualization comparison reveals that the ORF-attention features between lncRNAs and protein-coding transcripts are significantly distinct. The comparison results show that LncCat outperforms competing methods on several benchmark datasets. For Matthew's Correlation Coefficient (MCC), LncCat achieves 0.9503, 0.9219, 0.8591, 0.8672, and 0.9047 on the human, mouse, zebrafish, wheat, and chicken datasets, with improvements ranging from 1.90% to 7.82%, 1.49-17.63%, 6.11-21.50%, 3.02-51.64% and 5.35-26.90%, respectively. Moreover, LncCat dramatically improves the MCC by at least 11.90%, 12.96% and 42.61% on sORF test datasets of human, mouse, and zebrafish, respectively. Conclusions: Experiments indicate that LncCat performs better both on long ORF and sORF datasets, and ORF-attention features show positive effects on predicting lncRNA. In brief, LncCat is a reliable method for identifying lncRNA. Additionally, a user-friendly web server is developed for academics at http://cczubio.top/lnccat.

Meis1 Controls the Differentiation of Eye Progenitor Cells and the Formation of Posterior Poles during Planarian Regeneration.

As a member of TALE family, Meis1 has been proven to regulate cell proliferation and differentiation during cell fate commitment; however, the mechanism is still not fully understood. The planarian, which has an abundance of stem cells (neoblasts) responsible for regenerating any organ after injury, is an ideal model for studying the mechanisms of tissue identity determination. Here, we characterized a planarian homolog of Meis1 from the planarian Dugesia japonica. Importantly, we found that knockdown of DjMeis1 inhibits the differentiation of neoblasts into eye progenitor cells and results in an eyeless phenotype with normal central nervous system. Furthermore, we observed that DjMeis1 is required for the activation of Wnt signaling pathway by promoting the Djwnt1 expression during posterior regeneration. The silencing of DjMeis1 suppresses the expression of Djwnt1 and results in the inability to reconstruct posterior poles. In general, our findings indicated that DjMeis1 acts as a trigger for the activation of eye and tail regeneration by regulating the differentiation of eye progenitor cells and the formation of posterior poles, respectively.

Disruption of biofilms in periodontal disease through the induction of phase transition by cationic dextrans.

Biofilm of oral pathogenic microorganisms induced by their multiplication and coaggregation would lead to periodontitis. In biofilms, the extracellular polymeric substances (EPS) as a protective shield encapsulates the individual bacteria, protecting them against attack. To alleviate periodontal disease, disrupting the EPS of pathogenic bacteria is crucial and challenging. Based on the sufficient capacity of disorganizing EPS of our designed cationic dextrans, we hypothesized that these polymers could be competent in relieving periodontitis. We validated that cationic dextrans could induce the phase transition of EPS in biofilms, especially the Porphyromonas gingivalis (P. gingivalis), a keystone periodontal pathogen, thus effectively destroying biofilm in vitro. More importantly, satisfactory in vivo treatment was achieved in a rat periodontal disease model. In summary, the study exploited a practical and effective strategy to treat periodontitis with cationic dextrans' powerful biofilm-controlling potential. STATEMENT OF SIGNIFICANCE: Periodontal disease is closely related to dental plaque biofilms on the tooth surface. The biofilm forms gel structures and shields the bacteria underneath, thus protecting oral pathogens from traditional anti-bacterial reagents. Due to limited penetration into gel, the efficacy of these reagents in biofilm elimination is restricted. Our designed cationic dextran could wipe out the coverage of gel-like EPS to disperse encapsulated bacteria. Such superior capacity endowed them with satisfactory effect in disrupting biofilm. Notably, in a rat periodontitis model, cationic dextrans dramatically suppressed alveolar bone loss and alleviated periodontal inflammation by controlling dental plaque. Given the increasing global concerns about periodontal disease, it's worth expanding the application of cationic dextrans both scientifically and clinically.

Wearable in-sensor reservoir computing using optoelectronic polymers with through-space charge-transport characteristics for multi-task learning.

In-sensor multi-task learning is not only the key merit of biological visions but also a primary goal of artificial-general-intelligence. However, traditional silicon-vision-chips suffer from large time/energy overheads. Further, training conventional deep-learning models is neither scalable nor affordable on edge-devices. Here, a material-algorithm co-design is proposed to emulate human retina and the affordable learning paradigm. Relying on a bottle-brush-shaped semiconducting p-NDI with efficient exciton-dissociations and through-space charge-transport characteristics, a wearable transistor-based dynamic in-sensor Reservoir-Computing system manifesting excellent separability, fading memory, and echo state property on different tasks is developed. Paired with a 'readout function' on memristive organic diodes, the RC recognizes handwritten letters and numbers, and classifies diverse costumes with accuracies of 98.04%, 88.18%, and 91.76%, respectively (higher than all reported organic semiconductors). In addition to 2D images, the spatiotemporal dynamics of RC naturally extract features of event-based videos, classifying 3 types of hand gestures at an accuracy of 98.62%. Further, the computing cost is significantly lower than that of the conventional artificial-neural-networks. This work provides a promising material-algorithm co-design for affordable and highly efficient photonic neuromorphic systems.

Actin restricts cell proliferation and promotes differentiation during planarian regeneration.

Actin is an integral component of the cytoskeleton, which plays an important role in various fundamental cellular processes, such as affecting the polarity of embryonic cells during embryonic development in various model organisms. Meanwhile, previous studies have demonstrated that the polymerization of the actin cytoskeleton can affect cell migration, proliferation, and differentiation. Actin polymerization state regulated osteogenic differentiation and affected cell proliferation. However, the function of actin in regenerative biology has not been thoroughly elucidated. The planarian flatworm, which contains a large number of adult somatic stem cells (neoblasts), is an ideal model organism to study regenerative biology. Here, we identified a homolog of actin in planarian Dugesia japonica and found that RNAi targeting actin during planarian regeneration results in the formation of protrusions on the dorsal side, where the division of phospho-H3 mitotic cells is increased. In addition, a decrease in differentiation is observed in regenerating tissues after Djactin RNAi. These results indicate that Djactin functions in proliferation and differentiation control in planarian regeneration.

Long noncoding RNA NONMMUT015745 inhibits doxorubicin-mediated cardiomyocyte apoptosis by regulating Rab2A-p53 axis.

Doxorubicin (DOX) is an efficacious and widely used drug for human malignancy treatment, but its clinical application is limited due to side effects, especially cardiotoxicity. Our present study revealed that DOX could induce apoptosis in cardiomyocytes. Herein, we screened the dysregulated long noncoding RNAs (lncRNAs) in DOX-treated cardiomyocytes. Notably, overexpression of lncRNA NONMMUT015745 (lnc5745) could alleviate DOX-induced cardiomyocyte apoptosis both in vitro and in vivo. Conversely, silencing lnc5745 promotes cardiomyocyte apoptosis. Moreover, Rab2A, a direct target of lnc5745, possesses a protective effect in DOX-induced cardiotoxicity once knocked down. Importantly, we verified that the p53-related apoptotic signalling pathway was responsible for the lnc5745-mediated protective role against DOX-induced cardiomyocyte apoptosis. Mechanistically, Rab2A interacts with p53 and phosphorylated p53 on Ser 33 (p53 (Phospho-Ser 33)), promotes p53 phosphorylation, thereby activating the apoptotic pathway. Taken together, our results suggested that lnc5745 protects against DOX-induced cardiomyocyte apoptosis through suppressing Rab2A expression, modifying p53 phosphorylation, thereby regulating p53-related apoptotic signalling pathway. Our findings establish the functional mode of the lnc5745-Rab2A-p53 axis in DOX-induced cardiotoxicity. The development of new strategies targeting the lnc5745-Rab2A-p53 axis could attenuate DOX-induced cardiotoxicity, which is beneficial to its clinical anti-tumour application.

Insights Into Ferroptosis, a Novel Target for the Therapy of Cancer.

Ferroptosis is a new form of programmed cell death (PCD) characterized by an excess iron accumulation and subsequent unbalanced redox states. Ferroptosis is different from the already reported PCD and has unique morphological features and biochemical processes. Ferroptosis was first elaborated by Brent R. Stockwell's lab in 2012, in which small molecules erastin and RSL-3 induce PCD in Ras mutant cell lines. Ferroptosis involves various physiological processes and occurrence of disease and especially shows strong potential in cancer treatment. Development of small molecule compounds based on Stockwell's research was found to kill cancer cells, and some FDA-approved drugs were discovered to result in ferroptosis of cancer cells. Radiotherapy and checkpoint therapy have been widely used as a treatment for many types of cancer. Recently, some papers have reported that chemotherapy, radiotherapy, and checkpoint therapy induce ferroptosis of cancer cells, which provides new strategies for cancer treatment. Nevertheless, the limitless proliferation of tumor cells and the lack of cell death mechanisms are important reasons for drug resistance for tumor therapy. Therefore, we reviewed the molecular mechanism of ferroptosis and sensitivity to ferroptosis of different cancer cells and tumor treatment strategy.

PIWI-Interacting RNA HAAPIR Regulates Cardiomyocyte Death After Myocardial Infarction by Promoting NAT10-Mediated ac4 C Acetylation of Tfec mRNA.

PIWI-interacting RNAs (piRNAs) are abundantly expressed in heart. However, their functions and molecular mechanisms during myocardial infarction remain unknown. Here, a heart-apoptosis-associated piRNA (HAAPIR), which regulates cardiomyocyte apoptosis by targeting N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4 C) acetylation of transcription factor EC (Tfec) mRNA transcript, is identified. HAAPIR deletion attenuates ischemia/reperfusion induced myocardial infarction and ameliorate cardiac function compared to WT mice. Mechanistically, HAAPIR directly interacts with NAT10 and enhances ac4 C acetylation of Tfec mRNA transcript, which increases Tfec expression. TFEC can further upregulate the transcription of BCL2-interacting killer (Bik), a pro-apoptotic factor, which results in the accumulation of Bik and progression of cardiomyocyte apoptosis. The findings reveal that piRNA-mediated ac4 C acetylation mechanism is involved in the regulation of cardiomyocyte apoptosis. HAAPIR-NAT10-TFEC-BIK signaling axis can be potential target for the reduction of myocardial injury caused by cardiomyocyte apoptosis in ischemia heart diseases.

Destructing biofilms by cationic dextran through phase transition.

Eliminating biofilms from infected tissue presents one of the most challenging issues in clinical treatment of chronic wounds. In biofilms, the extracellular polymeric substances (EPS) form gel structures by electrostatic forces between macromolecules. We hypothesized that cationic polymers could induce the gel-to-sol phase transition of the network, leading to biofilms disruptions. We first validated this assumption by using polyethyleneimine (PEI) as a model molecule, and further synthesized two cationic dextrans with high biodegradability for in vitro and in vivo evaluation. All the cationic polymers could destruct Pseudomonas aeruginosa (P. aeruginosa) biofilms. Treating biofilm with cationic dextrans significantly enhanced the bacterial antibiotic sensitivity. When tested in a biofilm-presenting mouse wound healing model, the cationic dextrans efficiently controlled infection, and accelerated the healing process. Our findings suggest that devising cationic polymers to trigger phase transition of biofilm is an effective, straightforward, and perhaps generic strategy for anti-bacterial therapies.

The circRNA CNEACR regulates necroptosis of cardiomyocytes through Foxa2 suppression.

Circular RNAs (circRNAs) are differentially expressed in various cardiovascular disease including myocardial ischemia-reperfusion (I/R) injury. However, their functional impact on cardiomyocyte cell death, in particular, in necrotic forms of death remains elusive. In this study, we found that the level of mmu_circ_000338, a cardiac- necroptosis-associated circRNA (CNEACR), was reduced in hypoxia-reoxygenation (H/R) exposed cardiomyocytes and I/R-injured mice hearts. The enforced expression of CNEACR attenuated the necrotic form of cardiomyocyte death caused by H/R and suppressed of myocardial necrosis in I/R injured mouse heart, which was accompanied by a marked reduction of myocardial infarction size and improved cardiac function. Mechanistically, CNEACR directly binds to histone deacetylase (HDAC7) in the cytoplasm and interferes its nuclear entry. This leads to attenuation of HDAC7-dependent suppression of forkhead box protein A2 (Foxa2) transcription, which can repress receptor-interacting protein kinase 3 (Ripk3) gene by binding to its promoter region. In addition, CNEACR-mediated upregulation of FOXA2 inhibited RIPK3-dependent necrotic/necroptotic death of cardiomyocytes. Our study reveals that circRNAs such as CNEACR can regulate the cardiomyocyte necroptosis associated activity of HDACs, promotes cell survival and improves cardiac function in I/R-injured heart. Hence, the CNEACR/HDAC7/Foxa2/ RIPK3 axis could be an efficient target for alleviating myocardial damage caused by necroptotic death in ischemia heart diseases.

Honeysuckle-derived microRNA2911 inhibits tumor growth by targeting TGF-ß1.

BACKGROUND: Honeysuckle is a time-honored herb with anticancer activity in traditional Chinese medicine. Recently, accumulating reports are suggesting that the microRNAs in this medicinal plant not only play a physiological role in their original system, but also can be transmitted to another species as potential therapeutic components. In the numerous bioactive investigations, the anti-tumor effects of these microRNAs in the magical herb are rarely studied, especially the special miR2911, a honeysuckle-encoded atypical microRNA, with high stability during the boiling process and unique biological activity to target TGF-ß1 mRNA. METHODS: Luciferase assay was conducted to test the ability of miR2911 to target TGF-ß1 mRNA. ELISA was performed to determine the expression level of TGF-ß1 of mouse colorectal adenocarcinoma CT26 cells when treated with miR2911 and tumor tissue in Sidt1+/+ and Sidt1-/- mice. qRT-PCR was performed to examine the level of expression of miR2911. Tumor-bearing wild and nude mice were employed to evaluate the anti-tumor effect of honeysuckle and miR2911 in vivo. Tumor tissue necrosis was observed by H&E staining. Besides, the infiltration of T lymphocytes across solid tumors was tested by immunostaining staining. RESULTS: Our results showed that honeysuckle slowed the development of colon cancer down. Further research showed that miR2911 could bind strongly to TGF-ß1 mRNA and down-regulate the expression of TGF-ß1 and had a high stability under boiling and acid condition. Moreover, SIDT1 mediated dietary miR2911 inter-species absorption. And we found that miR2911 had a similar anticancer effect as honeysuckle. Mechanistically, miR2911 reversed the tumor-promoting effect of TGF-ß1 by an increase of T lymphocytes infiltration, resulting in slowing the colon cancer process in immunocompetent mice. Consistent with this inference, the anti-tumor effect of miR2911 was revealed to be abolished in T cell immune deficiency mice. CONCLUSION: Taken together, honeysuckle-derived miR2911 showed an anti-tumor effect in colon cancer through targeting TGF-ß1 mRNA. The down-regulation of TGF-ß1 promoted T lymphocytes infiltration, and accordingly impeded the colon tumor development.

Correction: Substrate-free and label-free electrocatalysis-assisted biosensor for sensitive detection of microRNA in lung cancer cells.

Correction for 'Substrate-free and label-free electrocatalysis-assisted biosensor for sensitive detection of microRNA in lung cancer cells' by Lin Cui et al., Chem. Commun., 2019, 55, 1172-1175.

Accelerated wound healing in diabetes by reprogramming the macrophages with particle-induced clustering of the mannose receptors.

The rate-limiting step in cutaneous wound healing, namely, the transition from inflammation to cell proliferation, depends on the high plasticity of macrophages to prevent inflammation in the wound tissues in a timely manner. Thus, strategies that reprogram inflammatory macrophages may improve the healing of poor wounds, particularly in the aged skin of individuals with diabetes or other chronic diseases. As shown in our previous study, KGM-modified SiO2 nanoparticles (KSiNPs) effectively activate macrophages to differentiate into the M2-type phenotype by inducing mannose receptor (MR) clustering on the cell surface. Here, we assess whether KSiNPs accelerate wound healing following acute or chronic skin injury. Using a full-thickness excision model in either diabetic mice or healthy mice, the wounds treated with KSiNPs displayed a dramatically increased closure rate and collagen production, along with decreased inflammation and increased angiogenesis in the regenerating tissues. Furthermore, KSiNPs induced the formation of M2-like macrophages by clustering MR on the cells. Accordingly, the cytokines produced by the KSiNP-treated macrophages were capable of inducing fibroblast proliferation and subsequent secretion of extracellular matrix (ECM). Based on these results, KSiNPs display great potential as an effective therapeutic approach for cutaneous wounds by effectively suppressing excessive or persistent inflammation and fibrosis.

Hydroxyethyl Starch-Based Nanoparticles Featured with Redox-Sensitivity and Chemo-Photothermal Therapy for Synergized Tumor Eradication.

Chemo-photothermal combination therapy could achieve synergistically enhanced efficiency against tumors. Nanocarriers with good safety and high efficiency for chemo- photothermal therapy are pressingly needed. A new type of hydroxyethyl starch (HES) based on nanoparticles (NPs) loaded with doxorubicin (DOX) and indocyanine green (ICG) was, thus, developed in this study. DOX-loaded HES conjugates with redox-sensitivity (HES-SS-DOX) were first synthesized and they were then combined with ICG to self-assemble into HES-SS-DOX@ICG NPs with controlled compositions and sizes via collaborative interactions. The optimal HES-SS-DOX@ICG NPs had good physical and photothermal stability in aqueous media and showed high photothermal efficiency in vivo. They were able to fast release the loaded DOX in response to the redox stimulus and the applied laser irradiation. Based on the H22-tumor-bearing mouse model, these NPs were found to tendentiously accumulate inside tumors in comparison to other major organs. The HES-SS-DOX@ICG NPs together with dose-designated laser irradiation were able to fully eradicate tumors with only one injection and one single subsequent laser irradiation on the tumor site during a 14-day treatment period. In addition, they showed almost no impairment to the body. The presently developed HES-SS-DOX@ICG NPs have good in vivo safety and highly efficient anti-tumor capability. These NPs in conjugation with laser irradiation have promising potential for chemo-photothermal cancer therapy in the clinic.