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By precisely controlling the waveform of ultrashort laser fields, electronic and nuclear motions in molecules can be steered on extremely short time scales, even in the attosecond regime. This new research field, termed "optochemistry", presents the light field in the time-frequency domain and opens new avenues for tailoring molecular reactions beyond photochemistry. This Perspective summarizes the ultrafast laser techniques employed in recent years for manipulating the molecular reactions based on waveform control of intense ultrashort laser pulses, where the chemical reactions can take place in isolated molecules, clusters, and various nanosystems. The underlying mechanisms for the coherent control of molecular dynamics are explicitly explored. Challenges and opportunities coexist in the field of optochemistry. Advanced technologies and theoretical modeling are still being pursued, with great prospects for controlling chemical reactions with unprecedented spatiotemporal precision.

Interlocked DNA nanostructures perform programmable movements in nanoscales such as sliding, contraction, and expansion. However, utilizing nanoscaled interlocked movements to regulate the functions of larger length scaled matrix and developing their applications has not yet been reported. Herein we describe the assembly of DNA-based daisy chain rotaxane nanostructure (DNA-DCR) composed of two hollow DNA nanostructures as macrocycles, two interlocked axles and two triangular prism-shaped DNA structures as stoppers, in which three mechanical states─fixed extended state (FES), sliding state (SS), and fixed contracted state (FCS)─are characterized by using toehold-mediated strand displacement reaction (SDR). The DNA-DCRs are further used as nanocomposites and introduced into hydrogel matrix to produce interlocked hydrogels, which shows modulable stiffness by elongating the interlocked axles to regulate the hydrogel swelling with hybridization chain reaction (HCR) treatment. Then the DCR-hydrogels are employed as dynamic biointerfaces for human mesenchymal stem cells (hMSCs) adhesion studies. First, hMSCs showed lower cell density on bare DCR-hydrogel treated with HCR-initiated swelling for stiffness decreasing. Second, the cell adhesion ligand (RGD) modified DNA-DCRs are constructed for hydrogel functionalization. DCR

Biopolymers, including DNA and peptides have been used as excellent self-assembling building blocks for programmable single-component or hybrid materials, due to their controlled molecular interactions. However, combining two assembling principles of DNA-based programmability and peptide-based specific molecular interactions for hybrid structures to microscale has not yet been achieved. In this study, we describe a hybrid microsystem that emerges from the co-assembly of DNA origami structure and short elastin-like polypeptide conjugated oligonucleotides, and initiates liquid-liquid phase separation to generate microdroplets upon heating above the transition temperature. Moreover, the hybrid microdroplets are capable for guest molecule trapping and perform bi-/tri-enzymatic cascades with rate enhancements as open “microreactors”. Our programmed assembled DNA-peptide microsystem represents a new combination of DNA nanotechnology and peptide science and opens potential application routes toward life-inspired biomaterials .

Diabetic patients with type 1 or advanced type 2 stages need timely and precise insulin injection to regulate the daily blood glucose levels (BGLs). Otherwise, risks of serious or even deadly diabetes-associated complications occur. To achieve prolonged glucose regulation and low hypoglycemia risks, a novel on-demand glucose-responsive glycopolymer system was constructed for insulin delivery, which was self-assembled into nanoparticles by dynamic covalent bonds between two polymers: fluorophenylboronic acid-grafted polymer (poly-F) and polyol polymer (poly-G). Insulin was loaded during the assembly process. The nanoparticles showed excellent glucose responsiveness

Diabetes is a metabolic disease that is affecting an ever-increasing number of people worldwide, resulting in increased burdens on healthcare systems and societies. Constant monitoring of blood glucose levels is required to prevent serious or even deadly complications. One major challenge of diabetes management is the simple and timely administration of insulin to facilitate consistent blood glucose regulation and reduce the incidence of hypoglycemia. With this research, we construct an insulin delivery system, the delivery system is comprised of phenylboronic acid based fluorescent probes, which is used as glucose responsive linkers, mesoporous silica nanoparticles providing an insulin reservoir, and zinc oxide nanoparticles used as gate keepers. The system with glucose sensitive responsive linker exhibits controlled release of insulin under high glucose concentrations, providing prolonged blood glucose regulation and no risks of hypoglycemia. Furthermore, the system is combined with a hyaluronic-acid based microneedle patch, which exhibit efficient skin penetration for transdermal delivery. With our system, the nanoparticles provide outstanding in vivo glucose regulation when administrated by subcutaneous injection or via transdermal microneedle patch. We anticipate that our biocompatible smart glucose responsive microneedle patch (SGRM patch) will facilitate the development of clinically useful systems.

Succinate dehydrogenase (SDH) is one of the most important molecular targets for the development of new fungicides. Carboxamide fungicides are a class of SDH inhibitors widely used to inhibit highly destructive plant pathogens. Although cases of resistance have been found in fungal pathogens due to the unrestricted use in recent years, there is still demand for new compounds with improved fungicidal activity. Therefore, a series of ester compounds were designed to investigate potential novel antifungal molecules. First, the antifungal activity of different benzyl alcohol compounds (

Novel xanthenoid dyes by replacing the central oxygen atom of the xanthene dyes with less electron-rich bridging groups have been intensively sought after primarily for their long spectral wavelengths. However, the new scaffolds are likely prone to nucleophilic attack at their central methane carbon, as the result of the reduced electron density of the fluorochromic scaffolds. We envisage that the bridging group may be harnessed to sterically shield the central methane carbon from incoming nucleophiles and render high stability and synthesized xantheno-xanthene dyes. Additionally, the xantheno-bridging group can be modified via electrophilic aromatic substitution to introduce functionalities, e.g., sulfonate groups.

Glutathione (GSH) plays a critical role in maintaining cellular redox homeostasis in biological system. Mitochondrion is a pivotal organelle for cellular aerobic respiration and its disorder is associated with impaired redox balance, leading to cell death. In this work, we designed and synthesized a non-invasive “off-on” mitochondrial-targeting fluorescent probe QZ for the detection of GSH in living cells. Based on the mechanism of native chemical ligation (NCL) and fluorescence resonance energy transfer (FRET), a rhodamine B derivative, QZ was prepared, by choosing aromatic thioester bond as the selective reaction site. QZ exhibited excellent detection capability for GSH over Cys and Hcy. Upon addition of GSH to QZ solution, a remarkably enhanced fluorescence was observed with a limit of detection of 2.98 μmol/L. Furthermore, QZ was found to possess the specific mitochondrial localization ability in cell imaging experiments. Moreover, with exogenous and endogenous stimulations, QZ could image GSH in living cells.

Vicinal dithiol-containing proteins (VDPs) are of considerable importance due to their role in regulating cellular functions through the reversible dithiol/disulfide inter-conversion reaction. However, there are currently no effective tools for the simultaneous tracing of endogenous VDPs in live cells. Here, we report an “off-on” fluorescent probe (RhQ) for the selective detection of VDPs and illustrate its utility for the long-term tracing of protein vicinal dithiols with simultaneous fluorescence imaging in various cell lines. Importantly, our study provides the first-time valuable insight into the localization of VDPs in whole cells, dynamically visualizing that presence of cell-surface protein vicinal dithiols in MCF-7 cells. Interestingly, some functional cell-surface VDPs have been reported for MCF-7 cells using proteomic analysis. Furthermore, the gradually released fluorescence from RhQ after its interaction with VDPs provides an overall picture of the cellular protein vicinal dithiol profile for different cell lines. This technology shows great promise as a visualization tool for revealing the role of cellular protein vicinal dithiols, especially VDPs on the cell-surface, and stimulating the design of VDP related drug candidates and vectors.

Ratiometric probes facilitate quantitative studies via self-calibration and are cherished for bioimaging. Often, a small probe-product spectral separation leads to crosstalk, but the rational devel...

OfChi-h, a lepidopteran-exclusive glycoside hydrolase family 18 (GH18) chitinase from the agricultural insect pest Ostrinia furnacalis, is a promising molecular target candidate for pest control and management. Berberine (BER), a traditional Chinese medicine, binds to a wide variety of glycosyl hydrolases via an identical mechanism, showing potential as a pesticide lead compound. In this work, we found that BER was a moderate inhibitor of OfChi-h with a Ki of 16.1 μM. To improve its efficacy, a series of BER derivatives featuring an ester bond linked to an aromatic or heterocyclic aromatic ring at the 9-position were designed and evaluated as effective OfChi-h inhibitors. The most potent compound, compound 19e with a nicotinate group, exhibited a Ki of 0.093 μM. Molecular docking analysis suggested that the common binding mode of BER derivatives featured a network of π-π stacking and electrostatic interactions and that the group at the 9-position enhanced the van der Waals and hydrogen bonding interactions. Administration of the BER derivative 19c to 4th-instar O. furnacalis larvae in an artificial diet led to their impaired growth and metamorphosis. This work provides a new starting point for the modification of BER for use in pest control.

Multi-modal combination therapy has attracted great attention, owing to the unsatisfactory therapeutic efficacy of conventional chemotherapy. Mesoporous silica-coated gold nanorods possess great potential in photothermal therapy and drug delivery. In this work, we fabricate a dual-responsive nanohybrid for combination treatment of the malignant tumor. In this system, gold nanorods are coated with the degradable mesoporous silica, and the chemotherapy drug doxorubicin (DOX) and photosensitizer (IR820) are co-loaded inside the pores of the silica. The encapsulation of hyaluronic acid (HA) endow the nanohybrids with mammary carcinoma targeting ability and better biocompatibility, owning to CD44+ receptor overexpressed in some cancer cells. As-prepared nanohybrids exhibit high responsiveness to a high glutathione (GSH) level and degrade rapidly in the presence of hyaluronidase (HAase) and GSH after endocytosis by 4T1 cells, allowing the efficient release of loaded DOX and IR 820 in tumor sites. Interestingly, near-infrared (NIR) laser not only triggers the generation of reactive oxygen species, but also remarkable photothermal efficacy originating from GNRs. Therefore, upon the irradiation of 808 nm NIR light, the combinatorial photodynamic, photothermal and chemotherapy is achieved, accordingly leading to a highly efficient antitumor outcome in vitro and in vivo. This strategy provides an ideal approach to constructing multimodal cancer therapy system. STATEMENT OF SIGNIFICANCE: • Dual-responsive nanohybrids for combinatorial therapy of breast cancer. • The nanohybrids exhibit both HAase and GSH stimuli-responsive behavior. • The nanohybrids exhibit light-activated PDT/PTT/chemotherapy. • The nanohybrids show good biosafety for potential clinical application.

Developing artificial microsystems based on liquid-liquid phase separation (LLPS) to mimic cellular dynamic compartmentalization has gained increasing attention. However, limitations including complicated components and laborious fabrication techniques have hindered their development. Herein, we describe a new single-component dynamic compartmentalization system using peptide-oligonucleotide conjugates (POCs) produced from short elastin-like polypeptides (sELPs) and oligonucleotides (ONs), which can perform thermoreversible phase transition between a nanovesicle and a microdroplet. The phase transition of sELP-ONs is thoroughly investigated, of which the transition temperature can be controlled by concentration, length of sELPs and ONs, base sequences, and salt. Moreover, the sELP-ON microcompartment can enrich a variety of functional molecules including small molecules, polysaccharides, proteins, and nucleic acids. Two sELP-ON compartments are used as nano- and microreactors for enzymatic reactions, separately, in which chemical activities are successfully regulated under different-scaled confinement effects, demonstrating their broad potential application in matter exchange and artificial cells.

Near-infrared (NIR) fluorophores absorbing maximally in the region beyond 800 nm, i.e., deep-NIR spectral region, are actively sought for biomedical applications. Ideal dyes are bright, nontoxic, photostable, biocompatible, and easily derivatized to introduce functionalities (e.g., for bioconjugation or aqueous solubility). The rational design of such fluorophores remains a major challenge. Silicon-substituted rhodamines have been successful for bioimaging applications in the red spectral region. The longer-wavelength silicon-substituted congeners for the deep-NIR spectral region are unknown to date. We successfully prepared four silicon-substituted bis-benzannulated rhodamine dyes (

Cyclin-dependent kinases play an important role in the regulation of cell cycle and transcription. Selective CDK4/6 inhibitors have been demonstrated to be effective in the treatment of cancer. In this article, we described the design and synthesis of a series of pteridine-7(8H)-one derivatives as dual CDK4/6 inhibitors. Among them, the most promising compound L2 exhibited significant inhibitory activity against CDK4 and CDK6 with IC

Nitric oxide donors (NODs) are indispensable in biological research and disease treatment. NODs had been utilized to treat cardiovascular diseases in clinic and many others are under trial. Thiols are typically required for these donors to release NO. Yet, their mechanism is complex and often lead to resistance. Herein, we reported that N-nitrosated electron-deficient dyes are capable of NO release with one-electron reduction. A fluorophore is generated simultaneously, whose fluorescence is harnessed to monitor the profile of NO release. Through electrochemical and spectral studies, NOD f3 was found to exhibit good biocompatibility and high reduction efficiency and its potentials in cell-protection in oxygen and glucose deprivation (OGD) models were showcased with endothelial cells. This work aims at offering a new approach to design reduction-triggered NOD, which have therapeutic potentials in ischemia-reperfusion.

A series of short intrinsically disordered polypeptide conjugated oligonucleotides (IDPOCs) were rationally developed and assembled into well-defined nanospheres. The nanospheres exhibited excellent reversible thermoresponsive regulation of their contraction and expansion. Furthermore, the nanospheres showed biocompatibility, drug encapsulation and effective cellular uptake.

By combining a Hill-type pH probe and a pH-insensitive naphthalimide fluorophore, we synthesized a FRET-based ratiometric pH probe (PHHF), exhibiting a reduced pH transition width, representing a unique approach for development of sensitive probes for detection of biorelevant pH changes.

Fluorophores with photo-modulatory fluorescence properties are valuable for cutting-edge localization microscopy. The existing probes are either photo-activatable, or photo-switchable, but not both. We report a probe (DH-SiR), a leuco-dye obtained by reduction of Si-rhodamine, with both photo-activatable and photo-switchable fluorescence. The potential for super-resolution microscopy was showcased.

Uni-directional multi-state fluorochromic scaffolds are valuable photofunctional molecules and yet scarce. We report a general approach for their design, i.e., mechanodonor-acceptor coupling (MDAC). A photochromic molecule is a mechanodonor, due to its capability to convert photonic energy into mechanical force. Upon proper coupling, it can be used to drive a mechanochromic molecule for uni-directional multi-state fluorochromism. The embodiment of this approach is a rhodamine-dithienylethylene hydride (RDH), which has been successfully employed in super-resolution localization microscopy

The pH-responsive profile of the traditional pH probes (the HH-type pH probes) is governed by the Henderson–Hasselbalch equation. Despite their widespread use, pH probes with further enhanced pH se...

A highly sensitive fluorescent sensor ZnDN was designed, synthesized and used for tracking intracellular zinc ions in various living cells and direct imaging of prostatic tissue in mice. ZnDN was prepared from the heterocyclic-fused naphthalimide fluorophore, and the zinc receptor, N,N-bis(2-pyridylmethyl)ethylenediamine (BPEN). Upon addition of Zn2+ to the solutions of ZnDN, a remarkable fluorescence enhancement was observed, which could be attributed to the photo-induced electron transfer (PET) mechanism. Since ZnDN exhibited high sensitivity toward Zn2+ in phosphate buffer solution, with a limit of detection of 4.0 × 10−9 mol/L, it was further applied for the imaging of exogenous and endogenous Zn2+ in different living cells. Living cells imaging experiments suggested that ZnDN could image the changes of intracellular free zinc ions, and could be used for two-photon imaging. Moreover, flow cytometry suggested that ZnDN could distinguish cancerous prostate cells from normal cells. Animal experiments indicated that ZnDN had the potential in imaging prostate tissue in vivo.

The balance between drug efficiency and its side effects on normal tissues is still a challenging problem to be solved in current cancer therapies. Among different strategies, cancer therapeutic methods based on nanomedicine delivery systems have received extensive attention due to their unique advantages such as improved circulation and reduced toxicity of drugs in the body. Herein, we constructed dual-responsive polymeric micelles DOXALS@MFM based on an upper critical solution temperature (UCST) polymer to simultaneously combine chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT). Amphiphilic block copolymer P(AAm

Ischemia-reperfusion (I/R) injuries are from the secondary radicals of ONOO