Cathepsin B Responsive Peptide-Purpurin Conjugates Assembly-Initiated in Situ Self-Aggregation for Cancer Sonotheranostics.

Sonodynamic therapy (SDT) was hampered by the sonosensitizers with low bioavailability, tumor accumulation, and therapeutic efficiency. In situ responsive sonosensitizer self-assembly strategy may provide a promising route for cancer sonotheranositics. Herein, an intelligent sonotheranostic peptide-purpurin conjugate (P18-P) is developed that can self-assemble into supramolecular structures via self-aggregation triggered by rich enzyme cathepsin B (CTSB). After intravenous injection, the versatile probe could achieve deep tissue penetration because of the penetration sequence of P18-P. More importantly, CTSB-triggered self-assembly strongly prolonged retention time, amplified photoacoustic imaging signal for sensitive CTSB detection, and boosted reactive oxygen species for advanced SDT, evoking specific CTSB responsive sonotheranostics. This peptide-purpurin conjugate may serve as an efficient sonotheranostic platform for the early diagnosis of CTSB activity and effective cancer therapy.

Metagenomic Next-Generation Sequencing Contributes to the Early Diagnosis of Mixed Infections in Central Nervous System.

Central nervous system (CNS) infections represent a challenge due to the complexities associated with their diagnosis and treatment, resulting in a high incidence rate and mortality. Here, we presented a case of CNS mixed infection involving Candida and human cytomegalovirus (HCMV), successfully diagnosed through macrogenomic next-generation sequencing (mNGS) in China. A comprehensive review and discussion of previously reported cases were also provided. Our study emphasizes the critical role of early pathogen identification facilitated by mNGS, underscoring its significance. Notably, the integration of mNGS with traditional methods significantly enhances the diagnostic accuracy of CNS infections. This integrated approach has the potential to provide valuable insights for clinical practice, facilitating early diagnosis, allowing for treatment adjustments, and ultimately, improving the prognosis for patients with CNS infections.

Metalloporphyrins as Catalytic Models for Studying Hydrogen and Oxygen Evolution and Oxygen Reduction Reactions.

The hydrogen evolution reaction (HER), oxygen evolution reaction (OER), and oxygen reduction reaction (ORR) are involved in biological and artificial energy conversions. H-H and O-O bond formation/cleavage are essential steps in these reactions. In nature, intermediates involved in the H-H and O-O bond formation/cleavage are highly reactive and short-lived, making their identification and investigation difficult. In artificial catalysis, the realization of these reactions at considerable rates and close to their thermodynamic reaction equilibria remains a challenge. Therefore, the elucidation of the reaction mechanisms and structure-function relationships is of fundamental significance to understand these reactions and to develop catalysts.This Account describes our recent investigations on catalytic HER, OER, and ORR with metalloporphyrins and derivatives. Metalloporphyrins are used in nature for light harvesting, energy conversion, electron transfer, O2 activation, and peroxide degradation. Synthetic metal porphyrin complexes are shown to be active for these reactions. We focused on exploring metalloporphyrins to study reaction mechanisms and structure-function relationships because they have stable and tunable structures and characteristic spectroscopic properties.For HER, we identified three H-H bond formation mechanisms and established the correlation between these processes and metal hydride electronic structures. Importantly, we provided direct experimental evidence for the bimetallic homolytic H-H bond formation mechanism by using sterically bulky porphyrins. Homolytic HER has been long proposed but rarely verified because the coupling of active hydride intermediates occurs spontaneously and quickly, making their detection challenging. By blocking the bimolecular mechanism through steric effects, we stabilized and characterized the NiIII-H intermediate and verified homolytic HER by comparing the reaction behaviors of Ni porphyrins with and without steric effects. We therefore provided an unprecedented example to control homolytic versus heterolytic HER mechanisms through tuning steric effects of molecular catalysts.For the OER, the water nucleophilic attack (WNA) on high-valent terminal Mn-oxo has been proposed for the O-O bond formation in natural and artificial water oxidation. By using Mn tris(pentafluorophenyl)corrole, we identified MnV(O) and MnIV-peroxo intermediates in chemical and electrochemical OER and provided direct experimental evidence for the Mn-based WNA mechanism. Moreover, we demonstrated several catalyst design strategies to enhance the WNA rate, including the pioneering use of protective axial ligands. By studying Cu porphyrins, we proposed a bimolecular coupling mechanism between two metal-hydroxide radicals to form O-O bonds. Note that late-transition metals do not likely form terminal metal-oxo/oxyl.For the ORR, we presented several strategies to improve activity and selectivity, including providing rapid electron transfer, using electron-donating axial ligands, introducing hydrogen-bonding interactions, constructing dinuclear cooperation, and employing porphyrin-support domino catalysis. Importantly, we used Co porphyrin atropisomers to realize both two-electron and four-electron ORR, representing an unparalleled example to control ORR selectivity by tuning only steric effects without modifying molecular and/or electronic structures.Lastly, we developed several strategies to graft metalloporphyrins on various electrode materials through different covalent bonds. The molecular-engineered materials exhibit boosted electrocatalytic performance, highlighting promising applications of molecular electrocatalysis. Taken together, this Account demonstrates the benefits of exploring metalloporphyrins for the HER, OER, and ORR. The knowledge learned herein is valuable for the development of porphyrin-based catalysts and also other molecular and material catalysts for small molecule activation reactions.

Ambient Ammonia Synthesis via Nitrate Electroreduction in Neutral Media on Fe3O4 Nanoparticles-decorated TiO2 Nanoribbon Array.

Electrochemical nitrate (NO3-) reduction is a potential approach to produce high-value ammonia (NH3) while removing NO3- pollution, but it requires electrocatalysts with high efficiency and selectivity. Herein, we report the development of Fe3O4 nanoparticles decorated TiO2 nanoribbon array on titanium plate (Fe3O4@TiO2/TP) as an efficient electrocatalyst for NO3--to-NH3 conversion. When operated in 0.1 M phosphate-buffered saline and 0.1 M NO3-, such Fe3O4@TiO2/TP achieves a prominent NH3 yield of 12394.3 µg h-1 cm-2 and a high Faradaic efficiency of 88.4%. In addition, it exhibits excellent stability during long-time electrolysis.

Higher magnetic susceptibility of globus pallidus in patients after macrocyclic GBCAs: assessment using quantitative susceptibility mapping.

BACKGROUND: As previous studies reported, gadolinium deposits in globus pallidus (GP) and dentate nucleus (DN) after repeated administrations of gadolinium-based contrast agents (GBCAs) and a signal intensity (SI) increase on T1-weighted images were related to linear GBCAs, not macrocyclic GBCAs. PURPOSE: To identify whether quantitative susceptibility mapping (QSM) could measure a subtle increase in magnetic susceptibility in DN and GP in patients after repeated administrations of gadoteric acid meglumine (Gd-DOTA). MATERIAL AND METHODS: In this study, 50 patients with cerebral tumors who had received at least three injections of Gd-DOTA (GBCA group) and 50 individuals without a history of GBCA injections (non-GBCA group) were included. The image data for QSM and T1-weighted images were reviewed. Spearman rank correlation was used to estimate the associations between the values (magnetic susceptibility of QSM and SI ratios of T1-weighted images) and the number of Gd-DOTA injections. RESULTS: The mean magnetic susceptibility of GP in GBCA group was 0.136 ± 0.031 ppm, which was significantly higher than that in control group (0.114 ± 0.030 ppm) (P = 0.001). In the GBCA group (n = 50), we found a substantial positive correlation between magnetic susceptibility of GP and the number of Gd-DOTA injections according to Spearman rank correlation coefficient (ρ = 0.673, P = 0.0001). There was a modest but significant correlation between magnetic susceptibility of DN and the number of Gd-DOTA injections (ρ = 0.311, P = 0.028). CONCLUSION: In comparison to the control group, the magnetic susceptibility of GP in the GBCA group was significantly higher and had a substantial positive association with the number of Gd-DOTA injections.

Phototheranostic Metal-Phenolic Networks with Antiexosomal PD-L1 Enhanced Ferroptosis for Synergistic Immunotherapy.

Tumor-derived exosome can suppress dendritic cells (DCs) and T cells functions. Excessive secretion of exosomal programmed death-ligand 1 (PD-L1) results in therapeutic resistance to PD-1/PD-L1 immunotherapy and clinical failure. Restored T cells by antiexosomal PD-L1 tactic can intensify ferroptosis of tumor cells and vice versa. Diminishing exosomal suppression and establishing a nexus of antiexosomal PD-L1 and ferroptosis may rescue the discouraging antitumor immunity. Here, we engineered phototheranostic metal-phenolic networks (PFG MPNs) by an assembly of semiconductor polymers encapsulating ferroptosis inducer (Fe3+) and exosome inhibitor (GW4869). The PFG MPNs elicited superior near-infrared II fluorescence/photoacoustic imaging tracking performance for a precise photothermal therapy (PTT). PTT-augmented immunogenic cell death relieved exosomal silencing on DC maturation. GW4869 mediated PD-L1 based exosomal inhibition revitalized T cells and enhanced the ferroptosis. This novel synergy of PTT with antiexosomal PD-L1 enhanced ferroptosis evoked potent antitumor immunity in B16F10 tumors and immunological memory against metastatic tumors in lymph nodes.

Ambient Ammonia Synthesis via Electrochemical Reduction of Nitrate Enabled by NiCo2 O4 Nanowire Array.

NiCo2 O4 nanowire array on carbon cloth (NiCo2 O4 /CC) is proposed as a highly active electrocatalyst for ambient nitrate (NO3 - ) reduction to ammonia (NH3 ). In 0.1 m NaOH solution with 0.1 m NaNO3 , such NiCo2 O4 /CC achieves a high Faradic efficiency of 99.0% and a large NH3 yield up to 973.2 µmol h-1  cm-2 . The superior catalytic activity of NiCo2 O4 comes from its half-metal feature and optimized adsorption energy due to the existence of Ni in the crystal structure. A Zn-NO3 - battery with NiCo2 O4 /CC cathode also shows a record-high battery performance.

Highly Efficient Bi4Ti3O12/g-C3N4/BiOBr Dual Z-Scheme Heterojunction Photocatalysts with Enhanced Visible Light-Responsive Activity for the Degradation of Antibiotics.

A novel Bi4Ti3O12/g-C3N4/BiOBr(BTO/CN/BOB) composite was synthesized by a solvothermal-mechanical mixed thermal method. The composition, structure, and micromorphology of the samples were analyzed. The BTO/CN/BOB composite photocatalyst shows better photocatalytic performance for tetracycline hydrochloride (TC) degradation compared to Bi4Ti3O12 and binary composite photocatalysts. The highest degradation rate of TC can reach 89.84% using the BTO/CN/BOB photocatalyst under the optimal conditions, and BTO/CN/BOB still exhibits good photocatalytic properties after recycling. Moreover, it also shows good photodegradation activity for different kinds of antibiotics, implying its wide application prospect. The photocatalytic performance and reuse stability of BTO/CN/BOB were significantly improved, which may be because of the enhanced spectral absorption range and efficient electron transfer capability by the synergistic effect and interaction among Bi4Ti3O12, BiOBr, and g-C3N4. Finally, the possible degradation pathway and electron transfer mechanism of the dual Z-scheme heterojunction are proposed.

High-Efficiency Ammonia Electrosynthesis on Anatase TiO2-x Nanobelt Arrays with Oxygen Vacancies by Selective Reduction of Nitrite.

Electrocatalytic reduction of nitrite to NH3 provides a new route for the treatment of nitrite in wastewater, as well as an attractive alternative to NH3 synthesis. Here, we report that an oxygen vacancy-rich TiO2-x nanoarray with different crystal structures self-supported on the Ti plate can be prepared by hydrothermal synthesis and by subsequently annealing it in an Ar/H2 atmosphere. Anatase TiO2-x (A-TiO2-x) can be a superb catalyst for the efficient conversion of NO2- to NH3; a high NH3 yield of 12,230.1 ± 406.9 µg h-1 cm-2 along with a Faradaic efficiency of 91.1 ± 5.5% can be achieved in a 0.1 M NaOH solution containing 0.1 M NaNO2 at -0.8 V, which also exhibits preferable durability with almost no decay of catalytic performances after cycling tests and long-term electrolysis. Furthermore, a Zn-NO2- battery with such A-TiO2-x as a cathode delivers a power density of 2.38 mW cm-2 as well as a NH3 yield of 885 µg h-1 cm-2.

Co Nanoparticles Decorated Corncob-Derived Biomass Carbon as an Efficient Electrocatalyst for Nitrate Reduction to Ammonia.

Nitrate (NO3-) is a type of common pollutant in aqueous systems. Electrochemical NO3- reduction is an ecofriendly and sustainable strategy, which can selectively reduce NO3- to highly value-added NH3 and remove NO3- pollutants at the same time. In this work, Co nanoparticles decorated corncob-derived biomass carbon as a highly active electrocatalyst for NO3- to NH3 conversion. Such a catalyst can achieve an amazing Faradaic efficiency of 93.4% and a large NH3 yield of 0.60 mmol h-1 cm-2 in alkaline media. 15N-Labeling experiment proves that the detected NH3 is derived from NO3- electroreduction. In addition, it also displays excellent durability in long-term and cycle-electrolysis tests.

A Metal-Phenolic Nanosensitizer Performs Hydrogen Sulfide-Reprogrammed Oxygen Metabolism for Cancer Radiotherapy Intensification and Immunogenicity.

Radiotherapy (RT) is hampered by the limited oxygen in tumors, which could be potentiated via reprogramming the oxygen metabolism and increasing the oxygen utilization efficiency. Herein, a metal-phenolic nanosensitizer (Hf-PSP-DTC@PLX) was integrated via an acid-sensitive hydrogen sulfide (H2 S) donor (polyethylene glycol-co-polydithiocarbamates, PEG-DTC) and a hafnium-chelated polyphenolic semiconducting polymer (Hf-PSP) in an amphiphilic polymer (poloxamer F127, PLX). Hf-PSP-DTC@PLX elicited a high imaging performance for precise RT and generated H2 S to reduce the cellular oxygen consumption rate via mitochondrial respiration inhibition, which reprogrammed the oxygen metabolism for improvement of the tumor oxygenation. Then, Hf-sensitization could fully utilize the well-preserved oxygen to intensify RT efficacy and activate immunogenicity. Such a synergistic strategy for improvement of oxygenation and oxygen utilization would have great potential in optimizing oxygen-dependent therapeutics.

Crucial Roles of a Pendant Imidazole Ligand of a Cobalt Porphyrin Complex in the Stoichiometric and Catalytic Reduction of Dioxygen.

A cobalt porphyrin complex with a pendant imidazole base ([(L1 )CoII ]) is an efficient catalyst for the homogeneous catalytic two-electron reduction of dioxygen by 1,1'-dimethylferrocene (Me2 Fc) in the presence of triflic acid (HOTf), as compared with a cobalt porphyrin complex without a pendant imidazole base ([(L2 )CoII ]). The pendant imidazole ligand plays a crucial role not only to provide an imidazolinium proton for proton-coupled electron transfer (PCET) from [(L1 )CoII ] to O2 in the presence of HOTf but also to facilitate electron transfer (ET) from [(L1 )CoII ] to O2 in the absence of HOTf. The kinetics analysis and the detection of intermediates in the stoichiometric and catalytic reduction of O2 have provided clues to clarify the crucial roles of the pendant imidazole ligand of [(L1 )CoII ] for the first time.

Recent Advances in Metal-Phenolic Networks for Cancer Theranostics.

Nanomedicine integrates different functional materials to realize the customization of carriers, aiming at increasing the cancer therapeutic efficacy and reducing the off-target toxicity. However, efforts on developing new drug carriers that combine precise diagnosis and accurate treatment have met challenges of uneasy synthesis, poor stability, difficult metabolism, and high cytotoxicity. Metal-phenolic networks (MPNs), making use of the coordination between phenolic ligands and metal ions, have emerged as promising candidates for nanomedicine, most notably through the service as multifunctional theranostic nanoplatforms. MPNs present unique properties, such as rapid preparation, negligible cytotoxicity, and pH responsiveness. Additionally, MPNs can be further modified and functionalized to meet specific application requirements. Here, the classification of polyphenols is first summarized, followed by the introduction of the properties and preparation strategies of MPNs. Then, their recent advances in biomedical sciences including bioimaging and anti-tumor therapies are highlighted. Finally, the main limitations, challenges, and outlooks regarding MPNs are raised and discussed.

Visible Light Response Photocatalytic Performance of Z-Scheme Ag3PO4/GO/UiO-66-NH2 Photocatalysts for the Levofloxacin Hydrochloride.

A Ag3PO4/GO/UiO-66-NH2(AGU) composite photocatalyst was prepared by an ultrasonic-assisted in situ precipitation method. The optical property, structure, composition, and morphology of photocatalysts were investigated using UV-vis diffuse reflectance spectroscopy, photoluminescence spectroscopy, electrochemical impedance spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, energy-dispersive spectrometry, transmission electron microscopy, Fourier transform infrared spectroscopy, and charge flow tracking by photodeposition of Pt and PbO2 nanoparticles. In comparison with Ag3PO4 and Ag3PO4/UiO-66-NH2(AU), the AGU composite photocatalyst showed heightened photocatalytic performance for the degradation of levofloxacin hydrochloride (LVF). The AGU photocatalyst (dosage: 0.8 g/L) with 1% mass content of graphene oxide (GO), the mass ratio of Ag3PO4 and UiO-66-NH2(U66N) reached 2:1, showed the highest photodegradation rate of 94.97% for 25 mg/L LVF after 60 min of visible light irradiation at pH = 6. The formation of a heterojunction and the addition of GO synergistically promote faster separation of electron-hole pairs, retain more active substances, and enhance the performance of the photocatalyst. Furthermore, the mechanism of the Z-scheme of the AGU composite photocatalytic is proposed.

Polyphenol-Based Nanomedicine Evokes Immune Activation for Combination Cancer Treatment.

Engineering multifunctional nanoplatforms with high therapeutic benefits has become a promising strategy for intractable cancer treatment. A novel polyphenol-based nanocomplex was designed to evoke highly efficacious cancer immunosurveillance while localizing therapy on the primary tumor and to minimize systemic side effects. This nanocomplex is prepared via metal-polyphenol coordination by encapsulating a natural polyphenol, gossypol, and a newly synthesized polyphenol derivative, polyethylene glycol-Chlorin e6 (Ce6). The combination of gossypol from cotton and the photosensitizer Ce6 can induce chemotherapeutic/photodynamic immunogenic cancer cell death upon laser irradiation, which is supported by a rich maturation of dendritic cells, concentrated secretion of inflammatory cytokines, and significant inhibition of distant untreated tumors. Finally, an assistance of the programmed-cell-death ligand-1 checkpoint-blockade immunotherapy can enhance the anti-tumor immune stimulation of our nanoplatform to a higher level.

Enzyme-Inspired Iron Porphyrins for Improved Electrocatalytic Oxygen Reduction and Evolution Reactions.

Nature uses Fe porphyrin sites for the oxygen reduction reaction (ORR). Synthetic Fe porphyrins have been extensively studied as ORR catalysts, but activity improvement is required. On the other hand, Fe porphyrins have been rarely shown to be efficient for the oxygen evolution reaction (OER). We herein report an enzyme-inspired Fe porphyrin 1 as an efficient catalyst for both ORR and OER. Complex 1, which bears a tethered imidazole for Fe binding, beats imidazole-free analogue 2, with an anodic shift of ORR half-wave potential by 160 mV and a decrease of OER overpotential by 150 mV to get the benchmark current density at 10 mA cm-2 . Theoretical studies suggested that hydroxide attack to a formal FeV =O form the O-O bond. The axial imidazole can prevent the formation of trans HO-FeV =O, which is less effective to form O-O bond with hydroxide. As a practical demonstration, we assembled rechargeable Zn-air battery with 1, which shows equal performance to that with Pt/Ir-based materials.

Efficient Polysulfide-Based Nanotheranostics for Triple-Negative Breast Cancer: Ratiometric Photoacoustics Monitored Tumor Microenvironment-Initiated H2 S Therapy.

The incidence of triple-negative breast cancer (TNBC) is difficult to predict, and TNBC has a high mortality rate among women worldwide. In this study, a theranostics approach is developed for TNBC with ratiometric photoacoustic monitored thiol-initiated hydrogen sulfide (H2 S) therapy. The ratiometric photoacoustic (PA) probe (CY) with a thiol-initiated H2 S donor (PSD) to form a nanosystem (CY-PSD nanoparticles) is integrated. In this theranostics approach, H2 S generated from PSD is sensed by CY based on ratiometric PA signals, which simultaneously pinpoints the tumor region. Additionally, H2 S is cytotoxic toward TNBC cells (MDA-MB 231), showing a tumor inhibition rate of 63%. To further verify its pharmacological mechanism, proteomics analysis is performed on tumors treated with CY-PSD nanoparticles. Cells are killed by the significant mitochondrial dysfunction via supressed energy supply and apoptosis initiation. Besides, the observed inhibition of oxidative stress also generates the cytotoxicity. Significant Kyoto Encyclopedia of Genes Genomes pathways related to TNBC are found to be inhibited. This H2 S theranostics approach updates the current anticancer therapies which brings promise for women suffering malignant breast cancer.

NIR II-Excited and pH-Responsive Ultrasmall Nanoplatform for Deep Optical Tissue and Drug Delivery Penetration and Effective Cancer Chemophototherapy.

The limited tumor tissue penetration of many nanoparticles remains a formidable challenge to their therapeutic efficacy. Although several photonanomedicines have been applied to improve tumor penetration, the first near-infrared window mediated by the low optical tissue penetration depth severely limits their anticancer effectiveness. To achieve deep optical tissue and drug delivery penetration, a near-infrared second window (NIR-II)-excited and pH-responsive ultrasmall drug delivery nanoplatform was fabricated based on BSA-stabilized CuS nanoparticles (BSA@CuS NPs). The BSA@CuS NPs effectively encapsulated doxorubicin (DOX) via strong electrostatic interactions to form multifunctional nanoparticles (BSA@CuS@DOX NPs). The BSA@CuS@DOX NPs had an ultrasmall size, which allowed them to achieve deeper tumor penetration. They also displayed stronger NIR II absorbance-mediated deep optical tissue penetration than that of the NIR I window. Moreover, the multifunctional nanoplatform preferentially accumulated in tumor sites, induced tumor hyperthermia, and generated remarkably high ROS levels in tumor sites upon NIR-II laser (1064 nm) irradiation. More importantly, our strategy achieved excellent synergistic effects of chemotherapy and phototherapy (chemophototherapy) under the guidance of photothermal imaging. The developed nanoparticles also showed good biocompatibility and bioclearance properties. Therefore, our work demonstrated a facile strategy for fabricating a multifunctional nanoplatform that is a promising candidate for deep tumor penetration as an effective antitumor therapy.

Dual Role of Doxorubicin for Photopolymerization and Therapy.

In this study, we report dual roles for doxorubicin (DOX), which can serve as an antitumor drug as well as a cocatalyst for a photoliving radical polymerization. DOX enhances the polymerization rates of a broad range of monomers, including acrylamide, acrylate, and methacrylates, allowing for high monomer conversion and well-defined molecular weights under irradiation with a blue light-emitting diode light (λmax = 485 nm, 2.2 mW/cm2). Utilizing this property, the photopolymerization of N,N-diethylacrylamide was performed in the presence of a poly(oligo(ethylene glycol) methyl ether acrylate) macroreversible addition-fragmentation chain transfer (macroRAFT) agent to prepare polymeric nanoparticles via aqueous polymerization-induced self-assembly (PISA). By varying the monomer:macroRAFT ratio, spherical polymeric nanoparticles of various diameters could be produced. Most notably, DOX was successfully encapsulated into the hydrophobic core of nanoparticles during the PISA process. The DOX-loaded nanoparticles were effectively uptaken into tumor cells and significantly inhibited the proliferation of tumor cells, demonstrating that the DOX bioactivity was not affected by the polymerization reaction.

Water-Soluble Polymers with Appending Porphyrins as Bioinspired Catalysts for the Hydrogen Evolution Reaction.

Molecular design to improve catalyst performance is significant but challenging. In enzymes, residue groups that are close to reaction centers play critical roles in regulating activities. Using this bioinspired strategy, three water-soluble polymers were designed with appending Co porphyrins and different side-chain groups to mimic enzyme reaction centers and activity-controlling residue groups, respectively. With these polymers, high hydrogen evolution efficiency was achieved in neutral aqueous media for electro- (turnover frequency >2.3×104  s-1 ) and photocatalysis (turnover number >2.7×104 ). Porphyrin units are surrounded and protected by polymer chains, and more importantly, the activity can be tuned with different side-chain groups. Therefore, instead of revising molecular structures that is difficult from both design and synthesis points of view, polymers can be used to improve molecular solubility and stability and simultaneously regulate activity by using side-chain groups.