Enhancing Human Treg Cell Induction through Engineered Dendritic Cells and Zinc Supplementation.

Regulatory T (Treg) cells hold promise for the ultimate cure of immune-mediated diseases. However, how to effectively restore Treg function in patients remains unknown. Previous reports suggest that activated dendritic cells (DCs) de novo synthesize locally high concentrations of 1,25-dihydroxy vitamin D, i.e., the active vitamin D or 1,25(OH)2D by upregulating the expression of 25-hydroxy vitamin D 1α-hydroxylase. Although 1,25(OH)2D has been shown to induce Treg cells, DC-derived 1,25(OH)2D only serves as a checkpoint to ensure well-balanced immune responses. Our animal studies have shown that 1,25(OH)2D requires high concentrations to generate Treg cells, which can cause severe side effects. In addition, our animal studies have also demonstrated that dendritic cells (DCs) overexpressing the 1α-hydroxylase de novo synthesize the effective Treg-inducing 1,25(OH)2D concentrations without causing the primary side effect of hypercalcemia (i.e., high blood calcium levels). This study furthers our previous animal studies and explores the efficacy of the la-hydroxylase-overexpressing DCs in inducing human CD4+FOXP3+regulatory T (Treg) cells. We discovered that the effective Treg-inducing doses of 1,25(OH)2D were within a range. Additionally, our data corroborated that the 1α-hydroxylase-overexpressing DCs synthesized 1,25(OH)2D within this concentration range in vivo, thus facilitating effective Treg cell induction. Moreover, this study demonstrated that 1α-hydroxylase expression levels were pivotal for DCs to induce Treg cells because physiological 25(OH)D levels were sufficient for the engineered but not parental DCs to enhance Treg cell induction. Interestingly, adding non-toxic zinc concentrations significantly augmented the Treg-inducing capacity of the engineered DCs. Our new findings offer a novel therapeutic avenue for immune-mediated human diseases, such as inflammatory bowel disease, type 1 diabetes, and multiple sclerosis, by integrating zinc with the 1α-hydroxylase-overexpressing DCs.

The role of ferroptosis in diabetic cardiovascular diseases and the intervention of active ingredients of traditional Chinese medicine.

Cardiovascular diseases (CVDs), encompassing ischaemic heart disease, cardiomyopathy, and heart failure, among others, are the most prevalent complications of diabetes and the leading cause of mortality in patients with diabetes. Cell death modalities, including apoptosis, necroptosis, and pyroptosis, have been demonstrated to be involved in the pathogenesis of CVDs. As research progresses, accumulating evidence also suggests the involvement of ferroptosis, a novel form of cell death, in the pathogenesis of CVDs. Ferroptosis, characterised by iron-dependent lipid peroxidation, which culminates in membrane rupture, may present new therapeutic targets for diabetes-related cardiovascular complications. Current treatments for CVDs, such as antihypertensive, anticoagulant, lipid-lowering, and plaque-stabilising drugs, may cause severe side effects with long-term use. Traditional Chinese medicine, with its broad range of activities and minimal side effects, is widely used in China. Numerous studies have shown that active components of Chinese medicine, such as alkaloids, polyphenols, and saponins, can prevent CVDs by regulating ferroptosis. This review summarises the recent findings on the regulatory mechanisms of active components of Chinese medicine against ferroptosis in CVDs, aiming to provide new directions and a scientific basis for targeting ferroptosis for the prevention and treatment of diabetic CVDs.

Zona incerta dopamine neurons encode motivational vigor in food seeking.

Energy deprivation triggers food seeking to ensure homeostatic consumption, but the neural coding of motivational vigor in food seeking during physical hunger remains unknown. Here, we report that ablation of dopamine (DA) neurons in zona incerta (ZI) but not ventral tegmental area potently impaired food seeking after fasting. ZI DA neurons and their projections to paraventricular thalamus (PVT) were quickly activated for food approach but inhibited during food consumption. Chemogenetic manipulation of ZI DA neurons bidirectionally regulated feeding motivation to control meal frequency but not meal size for food intake. Activation of ZI DA neurons promoted, but silencing of these neurons blocked, contextual memory associate with food reward. In addition, selective activation of ZI DA projections to PVT promoted food seeking for food consumption and transited positive-valence signals. Together, these findings reveal that ZI DA neurons encode motivational vigor in food seeking for food consumption through their projections to PVT.

PtSnBi Nanoplates Enable Photoacoustic Imaging-Guided Highly Efficient Photothermal Tumor Ablation.

The development of photothermal agents (PTAs) with robust photostability and high photothermal conversion efficiency is of great importance for cancer photothermal therapy. Herein, a novel PTA was created using two-dimensional intermetallic PtSnBi nanoplates (NPs), which demonstrated excellent photostability and biocompatibility with a high photothermal conversion efficiency of ∼61 % after PEGylation. More importantly, PtSnBi NPs could be employed as photoacoustic imaging contrast agents for tumor visualization due to their strong absorbance in the NIR range. In addition, both in vitro and in vivo experiments confirmed that PtSnBi NPs had a good photothermal efficacy under NIR laser irradiation. Therefore, the remarkable therapeutic characteristics of PtSnBi NPs make them a most promising candidate for cancer theranostics.

Characterization of the complete chloroplast genome of Veronica arvensis and its phylogenomic inference in plantaginaceae.

Veronica arvensis, which is an annual flowering plant in the plantain family Plantaginaceae, has commonly used as a Chinese herbal medicine to treat malaria in China. Here, the complete plastome of V. arvensis was successfully assembled based on genome skimming sequencing. The plastome of V. arvensis was 149,386 bp in length, comprising a pair of inverted repeats (IR; 24,946 bp) separated by a large single-copy (LSC) region (82,004 bp) and a small single-copy (SSC) region (17,490 bp). The plastid genome encoded 113 unique genes, consisting of 79 protein-coding genes, 30 tRNA genes, and four rRNA genes, with 19 duplicated genes in the IR regions. Six plastid hotspot regions (trnH-psbA, trnK-rps16, atpI-rps2, ndhF-rpl32, ccsA-ndhD and rps15-ycf1) were identified within Veronica. Phylogenetic analysis showed that the representative species from Veronica was monophyletic. V. persica and V. polita formed a maximum clade, followed by sister to V. arvensis.

Raphe serotonin projections dynamically regulate feeding behavior through targeting inhibitory circuits from rostral zona incerta to paraventricular thalamus.

OBJECTIVE: Rostral zona incerta (ZIR) evokes feeding by sending GABA transmission to paraventricular thalamus (PVT). Although central serotonin (5-HT) signaling is known to play critical roles in the regulation of food intake and eating disorders, it remains unknown whether raphe 5-HT neurons functionally innervate ZIR-PVT neural pathway for feeding control. Here, we sought to reveal how raphe 5-HT signaling regulates both ZIR and PVT for feeding control. METHODS: We used retrograde neural tracers to map 5-HT projections in Sert-Cre mice and slice electrophysiology to examine the mechanism by which 5-HT modulates ZIR GABA neurons. We also used optogenetics to test the effects of raphe-ZIR and raphe-PVT 5-HT projections on feeding motivation and food intake in mice regularly fed, 24 h fasted, and with intermittent high-fat high-sugar (HFHS) diet. In addition, we applied RNAscope in situ hybridization to identify 5-HT receptor subtype mRNA in ZIR. RESULTS: We show raphe 5-HT neurons sent projections to both ZIR and PVT with partial collateral axons. Photostimulation of 5-HT projections inhibited ZIR but excited PVT neurons to decrease motivated food consumption. However, both acute food deprivation and intermittent HFHS diet downregulated 5-HT inhibition on ZIR GABA neurons, abolishing the inhibitory regulation of raphe-ZIR 5-HT projections on feeding motivation and food intake. Furthermore, we found high-level 5-HT1a and 5-HT2c as well as low-level 5-HT7 mRNA expression in ZIR. Intermittent HFHS diet increased 5-HT7 but not 5-HT1a or 5-HT2c mRNA levels in the ZIR. CONCLUSIONS: Our results reveal that raphe-ZIR 5-HT projections dynamically regulate ZIR GABA neurons for feeding control, supporting that a dynamic fluctuation of ZIR 5-HT inhibition authorizes daily food intake but a sustained change of ZIR 5-HT signaling leads to overeating induced by HFHS diet.

Overcoming Hypoxia-Induced Ferroptosis Resistance via a 19 F/1 H-MRI Traceable Core-Shell Nanostructure.

Lipid peroxides accumulation induced ferroptosis is an effective cell death pathway for cancer therapy. However, the hypoxic condition of tumor microenvironment significantly suppresses the efficacy of ferroptosis. Here, we design a novel nanoplatform to overcome hypoxia-induced ferroptosis resistance. Specifically, we synthesize a novel kind of perfluorocarbon (PFOB)@manganese oxide (MnOx) core-shell nanoparticles (PM-CS NPs). Owing to the good carrier of O2 as fuel, PM-CS NPs can induce higher level of ROS generation, lipid peroxidation and GSH depletion, as well as lower activity of GPX4, compared with MnOx NPs alone. Moreover, the supplement of O2 can relieve tumor hypoxia to break down the storage of intracellular lipid droplets and increase expression of ACSL4 (a symbol for ferroptosis sensitivity). Furthermore, upon stimulus of GSH or acidity, PM-CS NPs exhibit the "turn on" 19 F-MRI signal and activatable T1 /T2 -MRI contrast for correlating with the release of Mn. Finally, PM-CS NPs exert high cancer inhibition rate for ferroptosis based therapy via synergetic combination of O2 -mediated enhancement of key pathways of ferroptosis.

Oxytocin Receptor-Expressing Neurons in the Paraventricular Thalamus Regulate Feeding Motivation through Excitatory Projections to the Nucleus Accumbens Core.

Oxytocin receptors (OTR) have been found in the paraventricular thalamus (PVT) for the regulation of feeding and maternal behaviors. However, the functional projections of OTR-expressing PVT neurons remain largely unknown. Here, we used chemogenetic and optogenetic tools to test the role of OTR-expressing PVT neurons and their projections in the regulation of food intake in both male and female OTR-Cre mice. We found chemogenetic activation of OTR-expressing PVT neurons promoted food seeking under trials with a progressive ratio schedule of reinforcement. Using Feeding Experimentation Devices for real-time meal measurements, we found chemogenetic activation of OTR-expressing PVT neurons increased meal frequency but not cumulative food intake because of a compensatory decrease in meal sizes. In combination with anterograde neural tracing and slice patch-clamp recordings, we found optogenetic stimulation of PVT OTR terminals excited neurons in the posterior basolateral amygdala (pBLA) and nucleus accumbens core (NAcC) as well as local PVT neurons through monosynaptic glutamatergic transmissions. Photostimulation of OTR-expressing PVT-NAcC projections promoted food-seeking, whereas selective activation of PVT-pBLA projections produced little effect on feeding. In contrast to selective activation of OTR terminals, photostimulation of a broader population of glutamatergic PVT terminals exerted direct excitation followed by indirect lateral inhibition on neurons in both NAcC and anterior basolateral amygdala. Together, these results suggest that OTR-expressing PVT neurons are a distinct population of PVT glutamate neurons that regulate feeding motivation through projections to NAcC.SIGNIFICANCE STATEMENT The paraventricular thalamus plays an important role in the regulation of feeding motivation. However, because of the diversity of paraventricular thalamic neurons, the specific neuron types promoting food motivation remain elusive. In this study, we provide evidence that oxytocin receptor-expressing neurons are a specific group of glutamate neurons that primarily project to the nucleus accumbens core and posterior amygdala. We found that activation of these neurons promotes the motivation for food reward and increases meal frequency through projections to the nucleus accumbens core but not the posterior amygdala. As a result, we postulate that oxytocin receptor-expressing neurons in the paraventricular thalamus and their projections to the nucleus accumbens core mainly regulate feeding motivation but not food consumption.

Degradable Magnetic Nanoplatform with Hydroxide Ions Triggered Photoacoustic, MR Imaging, and Photothermal Conversion for Precise Cancer Theranostic.

Theranostic agents based on inorganic nanomaterials are still suffered from the nonbiodegradable substances with long-term retention in body and unavoidable biological toxicity, as well as nonspecificity biodistribution with potential damage toward normal tissues. Here, we develop magnetic ions (FeIII, FeII, GdIII, MnII, and MnIII) coordinated nanoplatform (MICN) with framework structure and modify them with PEG (MICN-PEG). Notably, MICN-PEG demonstrates hydroxide ions (OH-) triggered the structure collapse along with responsive near-infrared photoacoustic (PA) signal, magnetic resonance imaging (MRI), and photothermal therapy (PTT) performances. Thereby, MICN-PEG is able to remain stable in tumors and exert excellent PA/MRI and PTT effects for multimodal imaging-guided cancer treatment. In contrast, MICN-PEG is gradually collapsed in normal tissues, resulting in the significant improvement of imaging accuracy and treatment specificity. MICN-PEG is gradually cleared after administration, minimizing concerns about the long-term toxicity.

Progress and Perspective of Solid-State Organic Fluorophores for Biomedical Applications.

Fluorescent organic dyes have been extensively used as raw materials for the development of versatile imaging tools in the field of biomedicine. Particularly, the development of solid-state organic fluorophores (SSOFs) in the past 20 years has exhibited an upward trend. In recent years, studies on SSOFs have focused on the development of advanced tools, such as optical contrast agents and phototherapy agents, for biomedical applications. However, the practical application of these tools has been hindered owing to several limitations. Thus, in this Perspective, we have provided insights that could aid researchers to further develop these tools and overcome the limitations such as limited aqueous dispersibility, low biocompatibility, and uncontrolled emission. First, we described the inherent photophysical properties and fluorescence mechanisms of conventional, aggregation-induced emissive, and precipitating SSOFs with respect to their biomedical applications. Subsequently, we highlighted the recent development of functionalized SSOFs for bioimaging, biosensing, and theranostics. Finally, we elucidated the potential prospects and limitations of current SSOF-based tools associated with biomedical applications.

Two-dimensional intermetallic PtBi/Pt core/shell nanoplates overcome tumor hypoxia for enhanced cancer therapy.

The design of multifunctional nanoplatforms is of great importance for improving hypoxia-induced therapeutic outcomes, especially for overcoming radiotherapy (RT) tolerance. Here, two-dimensional intermetallic PtBi/Pt nanoplates (PtBi NPs) were designed as a therapeutic platform to in situ generate oxygen, and thereby overcome tumor hypoxia for boosting photothermal/radiotherapy (PTT/RT). With high X-ray attenuation coefficient, PtBi NPs exhibited outstanding radiotherapy sensitization characteristics. Moreover, the high photothermal effect of PtBi NPs could promote the catalytic activity of PtBi NPs to achieve a synergistic PTT/RT effect. PEGylated PtBi NPs (PtBi-PEG) exhibited excellent biocompatibility, prolonged blood circulation time and enhanced tumor accumulation. Finally, PtBi-PEG showed excellent trimodal contrast enhancement for infrared (IR) imaging, photoacoustic (PA) imaging and X-ray imaging, facilitating imaging-guided cancer therapy. Thus, our work highlights PtBi-PEG as a novel multifunctional theranostic nanoplatform with great potential for future multimodal imaging-guided synergistic cancer therapy.

Serotonin activates paraventricular thalamic neurons through direct depolarization and indirect disinhibition from zona incerta.

Paraventricular thalamus (PVT) is a midline thalamic area that receives dense GABA projections from zona incerta (ZI) for the regulation of feeding behaviours. Activation of central serotonin (5-HT) signalling is known to inhibit food intake. Although previous studies have reported both 5-HT fibres and receptors in the PVT, it remains unknown how 5-HT regulates PVT neurons and whether PVT 5-HT signalling is involved in the control of food intake. Using slice patch-clamp recordings in combination with optogenetics, we found that 5-HT not only directly excited PVT neurons by activating 5-HT7 receptors to modulate hyperpolarization-activated cyclic nucleotide-gated (HCN) channels but also disinhibited these neurons by acting on presynaptic 5-HT1A receptors to reduce GABA inhibition. Specifically, 5-HT depressed photostimulation-evoked inhibitory postsynaptic currents (eIPSCs) in PVT neurons innervated by channelrhodopsin-2-positive GABA axons from ZI. Using paired-pulse photostimulation, we found 5-HT increased paired-pulse ratios of eIPSCs, suggesting 5-HT decreases ZI-PVT GABA release. Furthermore, we found that exposure to a high-fat-high-sucrose diet for 2 weeks impaired both 5-HT inhibition of ZI-PVT GABA transmission and 5-HT excitation of PVT neurons. Using retrograde tracer in combination with immunocytochemistry and slice electrophysiology, we found that PVT-projecting dorsal raphe neurons expressed 5-HT and were inhibited by food deprivation. Together, our study reveals the mechanism by which 5-HT activates PVT neurons through both direct excitation and indirect disinhibition from the ZI. The downregulation in 5-HT excitation and disinhibition of PVT neurons may contribute to the development of overeating and obesity after chronic high-fat diet. KEY POINTS: Serotonin (5-HT) depolarizes and excites paraventricular thalamus (PVT) neurons. 5-HT7 receptors are responsible for 5-HT excitation of PVT neurons and the coupling of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels to 5-HT receptors in part mediates the excitatory effect of 5-HT. 5-HT depresses the frequency of spontaneous inhibitory but not excitatory postsynaptic currents in PVT neurons. 5-HT1A receptors contribute to the depressive effect of 5-HT on inhibitory transmissions. 5-HT inhibits GABA release from zona incerta (ZI) GABA terminals in PVT. Chronic high-fat diet not only impairs 5-HT inhibition of the ZI-PVT GABA transmission but also downregulates 5-HT excitation of PVT neurons. PVT-projecting dorsal raphe neurons express 5-HT and are inhibited by food deprivation.

Oxytocin activation of paraventricular thalamic neurons promotes feeding motivation to attenuate stress-induced hypophagia.

The neuropeptide oxytocin (OT) regulates important brain functions including feeding through activating OT receptors in multiple brain areas. Both OT fibers and OT receptors have been reported in the paraventricular thalamus (PVT), an area that was revealed to be important for the control of emotion, motivation, and food intake. However, the function and modulation of PVT OT signaling remain unknown. Here, we used a progressive ratio (PR) schedule of reinforcement to examine the role of PVT OT signaling in regulating the motivation for food and patch-clamp electrophysiology to study the modulation of OT on PVT neurons in brain slices. We demonstrate that PVT OT administration increases active lever presses to earn food rewards in both male and female mice under PR trials and OT receptor antagonist atosiban inhibits OT-induced increase in motivated lever presses. However, intra-PVT OT infusion does not affect food intake in normal conditions but attenuates hypophagia induced by stress and anxiety. Using patch-clamp recordings, we find OT induces long-lasting excitatory effects on neurons in all PVT regions, especially the middle to posterior PVT. OT not only evokes tonic inward currents but also increases the frequency of spontaneous excitatory postsynaptic currents on PVT neurons. The excitatory effect of OT on PVT neurons is mimicked by the specific OT receptor agonist [Thr4, Gly7]-oxytocin (TGOT) and blocked by OT receptor antagonist atosiban. Together, our study reveals a critical role of PVT OT signaling in promoting feeding motivation to attenuate stress-induced hypophagia through exciting PVT neurons.

A Unique Multifunctional Luminescent Probe for Self-Monitoring Photodynamic Therapy by Detecting H2S in Cancer Cells.

With the increasing interest in photodynamic therapy (PDT), the assessment of the level of reactive oxygen species produced during PDT has also become increasingly important. However, most of the fluorescent probes for reactive oxygen species (ROS) evaluation were separated from photosensitizers in the PDT process, resulting in ex situ and asynchronous treatment feedback. Additionally, the consumption of ROS by these fluorescent probes themselves will inevitably affect the therapeutic effect. Herein, inspired by the redox balance in the cell, we developed a multifunctional hydrogen sulfide (H2S) probe Ru-NBD for reporting the therapeutic effect during the PDT process by detecting hydrogen sulfide. The probe Ru-NBD could not only serve as an effective PDT reagent both before and after H2S activation but could also be used for real-time and in situ monitoring of the therapeutic effect via restored luminescence during the PDT process. As the phototherapy process progresses, the luminescent signal of Ru-NBD changes accordingly. The experimental results show that there is a certain correlation between the luminescence intensity and the cell inhibition rate; thus, we can monitor the phototherapy process by detecting the changes in the probe's luminescent signal. This study provides an idea for the design and adjustment of PDT.

A two-photon fluorescence self-reporting black phosphorus nanoprobe for the in situ monitoring of therapy response.

The in situ and real-time supervision of reactive oxygen species (ROS) generated during photodynamic therapy (PDT) is of great significance for lessening nonspecific damage and guiding personalized therapy. However, photosensitizers frequently fail to deliver successful treatment accompanying the ROS-related imaging signals produced, impeding simple treatment outcome predictions and therapeutic schedule adjustments. Here, we report a two-photon fluorescence self-reporting strategy for the in situ and real-time monitoring of treatment response via a novel black phosphorus-based two-photon nanoprobe (TPBP). TPBP effectively generated singlet oxygen (1O2) under near-infrared laser irradiation for PDT, and 1O2 stimulated a two-photon molecule to emit fluorescence signals for feedback of 1O2 generation, which facilitated the regulation of treatment parameters to achieve precise and personalized medicine in deep tissue.

pH stimulus-disaggregated BODIPY: an activated photodynamic/photothermal sensitizer applicable to tumor ablation.

Herein, we report a pH stimulus-disaggregated BODIPY sensitizer (PTS) with low background-toxicity for achieving activated photodynamic/photothermal tumor therapy. Both the photodynamic and photothermal properties of PTS can be activated under acidic conditions, and PTS exhibits excellent antitumor properties, which is revealed by both in vitro and in vivo tests.

Oxygen-Embedded Quinoidal Acene Based Semiconducting Chromophore Nanoprobe for Amplified Photoacoustic Imaging and Photothermal Therapy.

Photoacoustic (PA) imaging as a noninvasive biomedical imaging technology exhibits high spatial resolution and deep tissue penetration for in vivo imaging. In order to fully explore the potential of PA imaging in biomedical applications, new contrast agents with improved PA stability and efficiency are in high demand. Herein, we present a new PA agent based on an oxygen-embedded quinoidal nonacene chromophore that is self-assembled into nanoparticles (Nano(O-Nonacene)-PEG), assisted by polyethylene glycol (PEG). Notably, the photothermal conversion efficiency of Nano(O-Nonacene)-PEG is 1.5 fold that of semiconducting polymer nanoparticles (Nano(PCPDTBT)-PEG) and 2.8 fold that of Au nanorods, owing to the low quantum yield of Nano(O-Nonacene)-PEG. Thereby, Nano(O-Nonacene)-PEG possess a greatly elevated PA signal intensity, compared to Nano(PCPDTBT)-PEG and Au nanorods, which have been widely explored for PA imaging. Due to the high resistance to photo bleaching, Nano(O-Nonacene)-PEG exhibits higher PA signal stability, which may be employed for long-term PA imaging. Moreover, when magnetic Zn0.4Fe2.6O4 nanoparticles are incorporated into Nano(O-Nonacene)-PEG, not only are magnetic resonance signals generated but also the photoacoustic efficacy is greatly enhanced. Therefore, Nano(O-Nonacene)-PEG offers distinct properties: (i) the elevated photoacoustic effect allows for high-resolution photoacoustic imaging, (ii) small size (10 nm in diameter) results in efficient tumor-targeting, and (iii) the facile application of efficient photothermal therapy in vivo. The current work offers the possibility of oxygen-embedded quinoidal acene as a promising PA probe for precision phototheranostics.

Nitric Oxide-Activated "Dual-Key-One-Lock" Nanoprobe for in Vivo Molecular Imaging and High-Specificity Cancer Therapy.

Cancer treatments are confounded by severe toxic effects toward patients. To address these issues, activatable nanoprobes have been designed for specific imaging and destruction of cancer cells under the stimulation of specific cancer-associated biomarkers. Most activatable nanoprobes were usually activated by some single-factor stimulation, but this restricts therapeutic specificity between diseased and normal tissue; therefore, multifactor activation is highly desired. To this end, we herein develop a novel dual-stimuli responsive theranostic nanoprobe for simultaneously activatable cancer imaging and photothermal therapy under the coactivation of "dual-key" stimulation of "nitric oxide (NO)/acidity", so as to further improve the therapeutic specificity. Specifically, we have integrated a weak electron acceptor (benzo[c][1,2,5]thiadiazole-5,6-diamine) into a donor-π-acceptor-π-donor type chromophore. When the weak acceptor was oxidized by NO in acidic conditions to form a stronger acceptor (5H-[1,2,3]triazolo[4,5-f]-2,1,3-benzothiadiazole), the molecule absorption was significantly increased in the near-infrared region, based on the intramolecular charge transfer (ICT) mechanism. Under the dual-key stimulation of NO/acidity within the tumor associated with inflammation, the nanoprobe can correspondingly output dual signals for ratiometric photoacoustic and photothermal imaging of cancer in vivo and do so with enhanced accuracy and specificity. Our novel nanoprobe exhibited higher photoacoustic signal enhancement under dual-factor activation at 9.8 times that of NO and 132 times that of acidity alone, respectively. Moreover, through such dual activation of NO/acidity, the nanoprobe produces more differentiation of hyperthermia between tumor and normal tissues, to afford satisfactory photothermal therapy with minimal toxic side effects. Thus, our work presents a promising strategy for significantly improving the precision and specificity of cancer imaging and therapy.

Lesson from Nature: Biomimetic Self-Assembling Phthalocyanines for High-Efficient Photothermal Therapy within the Biological Transparent Window.

Development of a facile but high-efficient small organic molecule-based photothermal therapy (PTT) in the in vivo transparent window (800-900 nm) has been regarded as a minimally invasive and most promising strategy for potential clinical cancer treatment. Phthalocyanine (Pc) molecules with remarkable photophysical and photochemical properties as well as high extinction coefficients in the near-infrared region are highly desirable for PTT, but as far satisfying single-component Pc-based PTT within the in vivo transparent window (800-900 nm) has very rarely been reported. Herein, inspired by the self-assembly algorithm of natural bacteriochlorophylls c, d, and e, biomimetic self-assembling tetrahexanoyl Pc Bio-ZnPc with outstanding light-harvesting capacity was demonstrated to exhibit excellent PTT efficacy evidenced by both in vitro and in vivo results, within the biological transparent window.

Optical Control of Metal Ion Probes in Cells and Zebrafish Using Highly Selective DNAzymes Conjugated to Upconversion Nanoparticles.

Spatial and temporal distributions of metal ions in vitro and in vivo are crucial in our understanding of the roles of metal ions in biological systems, and yet there is a very limited number of methods to probe metal ions with high space and time resolution, especially in vivo. To overcome this limitation, we report a Zn2+-specific near-infrared (NIR) DNAzyme nanoprobe for real-time metal ion tracking with spatiotemporal control in early embryos and larvae of zebrafish. By conjugating photocaged DNAzymes onto lanthanide-doped upconversion nanoparticles (UCNPs), we have achieved upconversion of a deep tissue penetrating NIR 980 nm light into 365 nm emission. The UV photon then efficiently photodecages a substrate strand containing a nitrobenzyl group at the 2'-OH of adenosine ribonucleotide, allowing enzymatic cleavage by a complementary DNA strand containing a Zn2+-selective DNAzyme. The product containing a visible FAM fluorophore that is initially quenched by BHQ1 and Dabcyl quenchers is released after cleavage, resulting in higher fluorescent signals. The DNAzyme-UCNP probe enables Zn2+ sensing by exciting in the NIR biological imaging window in both living cells and zebrafish embryos and detecting in the visible region. In this study, we introduce a platform that can be used to understand the Zn2+ distribution with spatiotemporal control, thereby giving insights into the dynamical Zn2+ ion distribution in intracellular and in vivo models.