An Integrated Arterial Remodeling Hydrogel for Preventing Restenosis After Angioplasty.

The high incidence of restenosis after angioplasty has been the leading reason for the recurrence of coronary heart disease, substantially increasing the mortality risk for patients. However, current anti-stenosis drug-eluting stents face challenges due to their limited functions and long-term safety concerns, significantly compromising their therapeutic effect. Herein, a stent-free anti-stenosis drug coating (denoted as Cur-NO-Gel) based on a peptide hydrogel is proposed. This hydrogel is formed by assembling a nitric oxide (NO) donor-peptide conjugate as a hydrogelator and encapsulating curcumin (Cur) during the assembly process. Cur-NO-Gel has the capability to release NO upon ß-galactosidase stimulation and gradually release Cur through hydrogel hydrolysis. The in vitro experiments confirmed that Cur-NO-Gel protects vascular endothelial cells against oxidative stress injury, inhibits cellular activation of vascular smooth muscle cells, and suppresses adventitial fibroblasts. Moreover, periadventitial administration of Cur-NO-Gel in the angioplasty model demonstrate its ability to inhibit vascular stenosis by promoting reendothelialization, suppressing neointima hyperplasia, and preventing constrictive remodeling. Therefore, the study provides proof of concept for designing a new generation of clinical drugs in angioplasty.

Genomic asymmetric epigenetic modification of transposable elements is involved in gene expression regulation of allopolyploid Brassica napus.

Polyploids are common and have a wide geographical distribution and environmental adaptability. Allopolyploidy may lead to the activation of transposable elements (TE). However, the mechanism of epigenetic modification of TEs in the establishment and evolution of allopolyploids remains to be explored. We focused on the TEs of model allopolyploid Brassica napus (An An Cn Cn ), exploring the TE characteristics of the genome, epigenetic modifications of TEs during allopolyploidization, and regulation of gene expression by TE methylation. In B. napus, approximately 50% of the genome was composed of TEs. TEs increased with proximity to genes, especially DNA transposons. TE methylation levels were negatively correlated with gene expression, and changes in TE methylation levels were able to regulate the expression of neighboring genes related to responses to light intensity and stress, which promoted powerful adaptation of allopolyploids to new environments. TEs can be synergistically regulated by RNA-directed DNA methylation pathways and histone modifications. The epigenetic modification levels of TEs tended to be similar to those of the diploid parents during the genome evolution of B. napus. The TEs of the An subgenome were more likely to be modified, and the imbalance in TE number and epigenetic modification level in the An and Cn subgenomes may lead to the establishment of subgenome dominance. Our study analyzed the characteristics of TE location, DNA methylation, siRNA, and histone modification in B. napus and highlighted the importance of TE epigenetic modifications during the allopolyploidy process, providing support for revealing the mechanism of allopolyploid formation and evolution.

NIR-II fluorescence and PA imaging guided activation of STING pathway in photothermal therapy for boosting cancer immunotherapy by theranostic thermosensitive liposomes.

Photothermal immunotherapy has shown great potential for efficient cancer treatment. However, the immunosuppressive tumor microenvironment forms a heavy barrier for photothermal-induced anti-tumor immunity by inhibiting dendritic cell (DC) maturation and cytotoxic T cell response. Moreover, the lack of reliable spatiotemporal imaging modalities makes photothermal immunotherapy difficult to guide tumor ablation and monitor therapeutic outcomes in real time. Herein, we designed a theranostic thermosensitive liposome (PLDD) as a versatile nanoplatform to boost the adaptive anti-tumor immunity of photothermal immunotherapy and to achieve multiple bioimaging modalities in a real-time manner. PLDD contains two major functional components: a multifunctional photothermal agent (DTTB) and an immune potentiator STING pathway agonist (DMXAA). Upon irradiation, the heat generated by DTTB induced the immunogenic cell death (ICD) of the tumor and dissociated the structure of thermosensitive liposome to release DMXAA, which ultimately activated the STING pathway and promoted the ICD-induced immune response by increasing DC cell maturation and T cell recruitment. Moreover, the DTTB in PLDD displayed excellent second near-infrared (NIR-II) fluorescence and photoacoustic (PA) dual-modal imaging, which provided omnibearing information on the tumor and guided the subsequent therapeutic operation. Therefore, this versatile PLDD with light-triggered promotion of anti-tumor immunity and multiple spatiotemporal imaging profiles holds great potential for the future development of cancer immunotherapy.

Navigations of the targeting pathway of nanomedicines toward tumor.

INTRODUCTION: Nanomedicines (NMs) have emerged as a promising approach for revolutionizing cancer treatment outcomes, mainly due to their benefits in the tumor-targeted delivery of therapeutics. The preferential accumulation of NMs in tumors has been widely verified by macroscopical technologies. Accordingly, several classic and emerging targeting mechanisms have been proposed to support the tumor-specific delivery of NMs. The targeting mechanism has been a topic of intense interest and controversy in the field of NMs development. Especially, the mechanisms by which NMs target tumor remain elusive. AREA COVERED: This topical review mainly discussed the evolution of the targeting mechanisms, crucial issues associated with each mechanism, and confused debates among the mechanisms. The targeting mechanisms of tumor-specific NMs discussed here include the enhanced permeability and retention (EPR) effect, protein corona-mediated targeting delivery, circulating cell mediated transportation, and transcytosis. EXPERT OPINION: It is of great significance for ultimate clinical translation to have more comprehensive considerations on the mechanism driving the pathway of NMs toward tumors. Our thoughts in this review are expected to provide a comprehensive understanding of the mechanisms and elicit thorough explorations of new mechanisms to renovate the knowledge framework of NMs delivery. [Figure: see text].

The impacts of allopolyploidization on Methyl-CpG-Binding Domain (MBD) gene family in Brassica napus.

BACKGROUND: Polyploidization promotes species formation and is widespread in angiosperms. Genome changes dramatically bring opportunities and challenges to plants after polyploidy. Methyl-CpG-Binding Domain (MBD) proteins can recognize and bind to methylation sites and they play an important role in the physiological process related to methylation in animals and plants. However, research on the influence of the allopolyploidization process on the MBD gene family is still lacking, so it is necessary to conduct a comprehensive analysis. RESULTS: In this study, twenty-two, ten and eleven MBD genes were identified in the genome of allotetraploid B. napus and its diploid ancestors, B. rapa and B. oleracea, respectively. Based on the clades of the MBD gene in Arabidopsis, rice and maize, we divided the new phylogenetic tree into 8 clades. Among them, the true MBD genes in Brassica existed in only 5 clades. Clade IV and Clade VI were unique in term of MBD genes in dicotyledons. Ka/Ks calculations showed that MBD genes underwent purifying selection in Brassica and may retain genes through sequence or functional differentiation early in evolution. In the process of allopolyploidization, the number of MBD gene introns increased, and the protein motifs changed. The MBD proteins had their own special motifs in each clade, and the MBD domains were only conserved in their clades. At the same time, the MBD genes were expressed in flower, leaf, silique, and stem tissues, and the expression levels of the different genes were significantly different, while the tissue specificity was not obvious. The allopolyploidization process may increase the number of cis-acting elements and activate the transposable elements. During allopolyploidization, the expression pattern of the MBD gene changes, which may be regulated by cis-acting elements and transposable elements. The number imbalance of cis-acting elements and transposable elements in An and Cn subgenomes may also lead to biased An subgenome expression of the MBD gene in B. napus. CONCLUSIONS: In this study, by evaluating the number, structure, phylogeny and expression of the MBD gene in B. napus and its diploid ancestors, we increased the understanding of MBD genes in allopolyploids and provided a reference for future analysis of allopolyploidization.

Amplifying Free Radical Generation of AIE Photosensitizer with Small Singlet-Triplet Splitting for Hypoxia-Overcoming Photodynamic Therapy.

Type-I photodynamic therapy (PDT) with less oxygen consumption shows great potential for overcoming the vicious hypoxia typically observed in solid tumors. However, the development of type-I PDT is hindered by insufficient radical generation and the ambiguous design strategy of type-I photosensitizers (PSs). Therefore, developing highly efficient type-I PSs and unveiling their structure-function relationship are still urgent and challenging. Herein, we develop two phenanthro[9,10-d]imidazole derivatives (AQPO and AQPI) with aggregation-induced emission (AIE) characteristics and boost their reactive oxygen species (ROS) generation efficiency by reducing singlet-triplet splitting (ΔEST). Both AQPO and AQPI show ultrasmall ΔEST values of 0.09 and 0.12 eV, respectively. By incorporating electron-rich anisole, the categories of generated ROS by AIE PSs are changed from type-II (singlet oxygen, 1O2) to type-I (superoxide anion radical, O2•- and hydroxyl radical, •OH). We demonstrate that the assembled AQPO nanoparticles (NPs) achieve a 3.2- and 2.9-fold increase in the O2•- and •OH generation efficiencies, respectively, compared to those of AQPI NPs (without anisole) in water, whereas the 1O2 generation efficiency of AQPO NPs is lower (0.4-fold) than that of AQPI NPs. The small ΔEST and anisole group endow AQPO with an excellent capacity for type-I ROS generation. In vitro and in vivo experiments show that AQPO NPs achieve an excellent hypoxia-overcoming PDT effect by efficiently eliminating tumor cells upon white light irradiation with good biosafety.

Stable π-radical nanoparticles as versatile photosensitizers for effective hypoxia-overcoming photodynamic therapy.

We report the first demonstration using a stable π-radical as a versatile photosensitizer for hypoxia-overcoming photodynamic therapy. After self-assembling the radical molecules into radical nanoparticles (NPs), the NPs show good water dispersibility, good biocompatibility, broad near-infrared (NIR) absorption and emission at ∼800 nm. Significantly, the radical NPs remain stable in various biological mediums, after 100 days exposure to the ambient environment, and even after long-term laser irradiation, which is superior to many reported radical-based materials. More importantly, upon 635 nm laser irradiation, sufficient superoxide radical (O2-˙) generation and in vitro cytotoxicity were observed addressing the most important hurdle for successful PDT in the oxygen-deficient tumor microenvironment. In addition, the radical NPs are also demonstrated to have effective in vivo PDT efficacy, and excellent biosafety.

Iron Self-Boosting Polymer Nanoenzyme for Low-Temperature Photothermal-Enhanced Ferrotherapy.

In this work, an iron self-boosting polymer nanoenzyme was prepared by using pyrrole-3-carboxylic acid as a monomer and iron as an oxidizing agent via a simple and one-step method [hereafter referred to as FePPy nanoparticles (NPs)]. In fact, researchers previously paid negligible attention on the iron element during the polymerization reaction of polypyrrole, thus the intrinsically catalytic functions and enzymatic activities of the high iron content (wt %: 21.11%) are ignored and not fully explored. As expected, results demonstrate that the as-synthesized FePPy NPs can decompose H2O2 to generate hydroxyl radicals (•OH) which exhibit enzyme characteristics, further inducing a nonapoptotic ferroptosis pathway. Moreover, the nanoenzyme shows impressive photothermal properties which can accelerate the Fenton reactions to enhance ferroptosis. The combined photothermal and ferroptosis therapy of FePPy NPs was found to have high efficacy. With the properties of easy synthesis, high efficacy, and good biocompatibility, the FePPy NPs are considered as potential agents for cancer treatments.

Achieving high singlet-oxygen generation by applying the heavy-atom effect to thermally activated delayed fluorescent materials.

A bromine-substituted thermally activated delayed fluorescent (TADF) molecule AQCzBr2 is designed with both small singlet-triplet splitting (ΔEST) and increased spin-orbit coupling (SOC) to boost intersystem crossing (ISC) for singlet oxygen generation. AQCzBr2 nanoparticles (NPs) demonstrate high productivity of singlet oxygen generation (ΦΔ = 0.91) which allows highly efficient photodynamic therapy toward cancer cells.

Single molecular nanomedicine with NIR light-initiated superoxide radical, singlet oxygen and thermal generation for hypoxia-overcoming cancer therapy.

While photodynamic therapy (PDT) of cancer has attracted much recent attention, its general applications are limited by the shallow tissue penetration depth of short-wavelength photons and the low oxygen contents in typical solid tumors. Herein, we develop small molecule (BthB)-based nanoparticles (NPs) which not only generate heat for effective photothermal therapy (PTT), but also generate superoxide radicals (O2˙-) for hypoxia-overcoming photodynamic therapy (PDT) upon irradiation with an 808 nm laser. To the best of our knowledge, there are few reports of organic PDT agents which can work in hypoxia upon irradiation with photons having wavelengths longer than 800 nm. With the merits of NIR-excitability for better penetration depth, the BthB NPs are demonstrated both in vitro and in vivo to be highly effective for cancer ablation.

Water-Splitting Based and Related Therapeutic Effects: Evolving Concepts, Progress, and Perspectives.

Water-splitting has been extensively studied especially for energy applications. It is often not paid with enough attention for biomedical applications. In fact, several innovative breakthroughs have been achieved in the past few years by employing water-splitting for treating cancer and other diseases. Interestingly, among these important works, only two reports have mentioned the term "water-splitting." For this reason, the importance of water-splitting for biomedical applications is significantly underestimated. This progress work is written with the aims to explain and summarize how the principle of water-splitting is employed to achieve therapeutic results not offered by conventional approaches. It is expected that this progress report will not only explain the importance of water-splitting to scientists in the biomedical fields, it should also draw attention from scientists working on energy applications of water-splitting.

Single-Photomolecular Nanotheranostics for Synergetic Near-Infrared Fluorescence and Photoacoustic Imaging-Guided Highly Effective Photothermal Ablation.

Multi-modality imaging-guided cancer therapy is considered as a powerful theranostic platform enabling simultaneous precise diagnosis and treatment of cancer. However, recently reported multifunctional systems with multiple components and sophisticate structures remain major obstacles for further clinical translation. In this work, a single-photomolecular theranostic nanoplatform is fabricated via a facile nanoprecipitation strategy. By encapsulating a semiconductor oligomer (IT-S) into an amphiphilic lipid, water-dispersible IT-S nanoparticles (IT-S NPs) are prepared. The obtained IT-S NPs have a very simple construction and possess ultra-stable near-infrared (NIR) fluorescence (FL)/photoacoustic (PA) dual-modal imaging and high photothermal conversion efficiency of 72.3%. Accurate spatiotemporal distribution profiles of IT-S NPs are successfully visualized by NIR FL/PA dual-modal imaging. With the comprehensive in vivo imaging information provided by IT-S NPs, tumor photothermal ablation is readily realized under precise manipulation of laser irradiation, which greatly improves the therapeutic efficacy without any obvious side effects. Therefore, the IT-S NPs allow high tumor therapeutic efficacy under the precise guidance of FL/PA imaging techniques and thus hold great potential as an effective theranostic platform for future clinical applications.

Stable Organic Photosensitizer Nanoparticles with Absorption Peak beyond 800 Nanometers and High Reactive Oxygen Species Yield for Multimodality Phototheranostics.

Effective multimodality phototheranostics under deep-penetration laser excitation is highly desired for tumor medicine, which is still at a deadlock due to lack of versatile photosensitizers with absorption located in the long-wavelength region. Herein, we demonstrate a stable organic photosensitizer nanoparticle based on molecular engineering of benzo[c]thiophene (BT)-based photoactivated molecules with strong wavelength-tunable absorption in the near-infrared region. Via molecular design, the absorption and singlet oxygen generation of BT molecules would be reliably tuned. Importantly, the nanoparticles with a red-shifted absorption peak of 843 nm not only show over 10-fold reactive oxygen species yield compared with indocyanine green but also demonstrate a notable photothermal effect and photoacoustic signal upon 808 nm excitation. The in vitro and in vivo experiments substantiate good multimodal anticancer efficacy and imaging performance of BT theranostics. This work provides an organic photosensitizer nanoparticle with long-wavelength excitation and high photoenergy conversion efficiency for multimodality phototherapy.

Transcriptomic analysis of Verbena bonariensis roots in response to cadmium stress.

BACKGROUND: Cadmium (Cd) is a serious heavy metal (HM) soil pollutant. To alleviate or even eliminate HM pollution in soil, environmental-friendly methods are applied. One is that special plants are cultivated to absorb the HM in the contaminated soil. As an excellent economical plant with ornamental value and sound adaptability, V. bonariensis could be adapted to this very situation. In our study, the Cd tolerance in V. bonariensis was analyzed as well as an overall analysis of transcriptome. RESULTS: In this study, the tolerance of V. bonariensis to Cd stress was investigated in four aspects: germination, development, physiological changes, and molecular alterations. The results showed that as a non-hyperaccumulator, V. bonariensis did possess the Cd tolerance and the capability to concentration Cd. Under Cd stress, all 237, 866 transcripts and 191, 370 unigenes were constructed in the transcriptome data of V. bonariensis roots. The enrichment analysis of gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway revealed that differentially expressed genes (DEGs) under Cd stress were predominately related to cell structure, reactive oxygen species (ROS) scavenging system, chelating reaction and secondary metabolites, transpiration and photosynthesis. DEGs encoding lignin synthesis, chalcone synthase (CHS) and anthocyanidin synthase (ANS) were prominent in V. bonariensis under Cd stress. The expression patterns of 10 DEGs, validated by quantitative real-time polymerase chain reaction (qRT-PCR), were in highly accordance with the RNA-Sequence (RNA-Seq) results. The novel strategies brought by our study was not only benefit for further studies on the tolerance of Cd and functional genomics in V. bonariensis, but also for the improvement molecular breeding and phytoremediation.

Biodegradable π-Conjugated Oligomer Nanoparticles with High Photothermal Conversion Efficiency for Cancer Theranostics.

We developed a biodegradable photothermal therapeutic (PTT) agent, π-conjugated oligomer nanoparticles (F8-PEG NPs), for highly efficient cancer theranostics. By exploiting an oligomer with excellent near-infrared (NIR) absorption, the nanoparticles show a high photothermal conversion efficiency (PCE) up to 82%, surpassing those of reported inorganic and organic PTT agents. In addition, the oligomer nanoparticles show excellent photostability and good biodegradability. The F8-PEG NPs are also demonstrated to have excellent biosafety and PTT efficacy both in vitro and in vivo. This contribution not only proposes a promising oligomer-based PTT agent but also provides insight into developing highly efficient nanomaterials for cancer theranostics.

The Nanoassembly of an Intrinsically Cytotoxic Near-Infrared Dye for Multifunctionally Synergistic Theranostics.

The combination of diagnostic and therapeutic functions in a single theranostic nanoagent generally requires the integration of multi-ingredients. Herein, a cytotoxic near-infrared (NIR) dye (IR-797) and its nanoassembly are reported for multifunctional cancer theranostics. The hydrophobic IR-797 molecules are self-assembled into nanoparticles, which are further modified with an amphiphilic polymer (C18PMH-PEG5000) on the surface. The prepared PEG-IR-797 nanoparticles (PEG-IR-797 NPs) possess inherent cytotoxicity from the IR-797 dye and work as a chemotherapeutic drug which induces apoptosis of cancer cells. The IR-797 NPs are found to have an ultrahigh mass extinction coefficient (444.3 L g-1 cm-1 at 797 nm and 385.9 L g-1 cm-1 at 808 nm) beyond all reported organic nanomaterials (<40 L g-1 cm-1 ) for superior photothermal therapy (PTT). In addition, IR-797 shows some aggregation-induced-emission (AIE) properties. Combining the merits of good NIR absorption, high photothermal energy conversion efficiency, and AIE, makes the PEG-IR-797 NPs useful for multimodal NIR AIE fluorescence, photoacoustic, and thermal imaging-guided therapy. The research exhibits the possibility of using a single ingredient and entity to perform multimodal NIR fluorescence, photoacoustic, and thermal imaging-guided chemo-/photothermal combination therapy, which may trigger wide interest from the fields of nanomedicine and medicinal chemistry to explore multifunctional theranostic organic molecules.

Dual Fenton Catalytic Nanoreactor for Integrative Type-I and Type-II Photodynamic Therapy Against Hypoxic Cancer Cells.

Tumor hypoxia is a noteworthy impediment to effective photodynamic therapy (PDT), as it would sharply weaken the effectiveness of oxygen-dependent PDT. To enable effective PDT in both hypoxia as well as normoxia circumstances, here, we report a multifunctional nanoreactor (C3N4/MnO2 NPs), which guarantees effective type-II PDT (oxygen-dependent) in hypoxia by in situ oxygen generation via the Fenton reaction. In addition, the C3N4/MnO2 NPs can also be used for oxygen-independent type-I PDT by evolving the cytotoxic hydroxyl radical to reduce reliance on intracellular oxygen content. In vitro cytotoxicity assays made evident that the C3N4/MnO2 NPs exhibit a much higher cancer-cell-killing ability than C3N4 NPs not only in normoxia but also in hypoxic circumstances. The smart integration of type-I and type-II PDT into the therapeutic nanoplatform enables effective PDT even though intracellular oxygen is not satisfactory.

The impact of light irradiation timing on the efficacy of nanoformula-based photo/chemo combination therapy.

Photo/chemo combination therapy has been demonstrated to be a generally more powerful strategy for treating cancers than a single treatment modality. However, it is unknown whether the timing of light irradiation has any impact on therapeutic efficacy. We designed a carrier-free and self-monitoring nanodrug to monitor the entire dual-drug release profile and determined the impact of photodynamic therapy (PDT) at different time points. The designed nanodrug consists of the chemotherapeutic doxorubicin (DOX) and the photosensitizer pheophorbide A (PhA). The drugs form a fluorescence resonance energy transfer (FRET) pair (DOX transferring energy to PhA) when present at a precise ratio in the combination nanodrug. Due to the FRET effect, the DOX-PhA nanoparticles (NPs) show PhA fluorescence in a normal pH environment (such as cytoplasm). However, the FRET effect is lost when the NPs are disassembled in an acidic environment (such as lysosomes), and the DOX fluorescence is recovered. By real-time fluorescence variation monitoring, we determined the key time points when the drugs reached various subcellular locations, which helped us to determine the PDT-triggering time points and investigate the impact on the therapeutic effect in the combination therapy. Furthermore, the PDT was triggered at these established time points both in vitro and in vivo, which revealed that the best PDT-triggering time point in the combination therapy was achieved after nuclear entry of DOX. The study suggests that the optimization of combination therapy, not only photo/chemo but also chemo/chemo combination therapy, may require not only a controlled drug ratio but also a controlled drug release profile and target arrival time.

The adverse vascular effects of multi-walled carbon nanotubes (MWCNTs) to human vein endothelial cells (HUVECs) in vitro: role of length of MWCNTs.

BACKGROUND: Increasing evidences indicate that exposure to multi-walled carbon nanotubes (MWCNTs) could induce adverse vascular effects, but the role of length of MWCNTs in determining the toxic effects is less studied. This study investigated the adverse effects of two well-characterized MWCNTs to human umbilical vein endothelial cells (HUVECs). METHODS: The internalization and localization of MWCNTs in HUVECs were examined by using transmission electron microscopy (TEM). The cytotoxicity of MWCNTs to HUVECs was assessed by water soluble tetrazolium-8 (WST-8), lactate dehydrogenase (LDH) and neutral red uptake assays. Oxidative stress was indicated by the measurement of intracellular glutathione (GSH) and reactive oxygen species (ROS). ELISA was used to determine the release of inflammatory cytokines. THP-1 monocyte adhesion to HUVECs was also measured. To indicate the activation of endoplasmic reticulum (ER) stress, the expression of ddit3 and xbp-1s was measured by RT-PCR, and BiP protein level was measured by Western blot. RESULTS: Transmission electron microscopy observation indicates the internalization of MWCNTs into HUVECs, with a localization in nuclei and mitochondria. The longer MWCNTs induced a higher level of cytotoxicity to HUVECs compared with the shorter ones. Neither of MWCNTs significantly promoted intracellular ROS, but the longer MWCNTs caused a higher depletion of GSH. Exposure to both types of MWCNTs significantly promoted THP-1 adhesion to HUVECs, accompanying with a significant increase of release of interleukin-6 (IL-6) but not tumor necrosis factor α (TNFα), soluble ICAM-1 (sICAM-1) or soluble VCAM-1 (sVCAM-1). Moreover, THP-1 adhesion and release of IL-6 and sVCAM-1 induced by the longer MWCNTs were significantly higher compared with the responses induced by the shorter ones. The biomarker of ER stress, ddit3 expression, but not xbp-1s expression or BiP protein level, was significantly induced by the exposure of longer MWCNTs. CONCLUSIONS: Combined, these results indicated length dependent toxic effects of MWCNTs to HUVECs in vitro, which might be associated with oxidative stress and activation of ER stress.