Demethylation C-C coupling reaction facilitated by the repulsive Coulomb force between two cations.

Carbon chain elongation (CCE) is normally carried out using either chemical catalysts or bioenzymes. Herein we demonstrate a catalyst-free approach to promote demethylation C-C coupling reactions for advanced CCE constructed with functional groups under ambient conditions. Accelerated by the electric field, two organic cations containing a methyl group (e.g., ketones, acids, and aldehydes) approach each other with such proximity that the energy of the repulsive Coulomb interaction between these two cations exceeds the bond energy of the methyl group. This results in the elimination of a methyl cation and the coupling of the residual carbonyl carbon groups. As confirmed by high-resolution mass spectrometry and isotope-labeling experiments, the C-C coupling reactions (yields up to 76.5%) were commonly observed in the gas phase or liquid phase, for which the mechanism was further studied using molecular dynamics simulations and stationary-point calculations, revealing deep insights and perspectives of chemistry.

Thermodynamic Reversal and Structural Correlation of 24-Crown-8/Protonated Tryptophan and 24-Crown 8/Protonated Serine Noncovalent Complexes in the Gas Phase vs in Solution: Quantum Chemical Analysis.

We investigate the structures of 24-crown-8/H+/l-tryptophan (CR/TrpH+) and 24-crown-8/H+/l-serine (CR/SerH+) noncovalent host-guest complex both in the gas phase and in an aqueous solution by quantum chemical methods. The Gibbs free energies of the complex in the two phases are calculated to determine the thermodynamically most favorable conformer in each phase. Our predictions indicate that both the carboxyl and the ammonium in CR/TrpH+ and the ammonium in the CR/SerH+ complexes in the lowest Gibbs free energy configurations form hydrogen bonds (H-bonds) with the CR host in the gas phase, while the conformer with the "naked" (devoid of H-bond with the CR host) -CO2H (and/or -OH) is much less favorable (Gibbs free energy higher by >3.6 kcal/mol). In the solution phase, however, a "thermodynamic reversal" occurs, making the higher Gibbs free energy gas-phase CR/TrpH+ and CR/SerH+ conformers thermodynamically more favorable under the influence of solvent molecules. Consequently, the global minimum Gibbs free energy structure in solution is structurally correlated with the thermodynamically much less gas-phase conformer. Discussions are provided concerning the possibility of elucidating host-guest-solvent interactions in solution from the gas-phase host-guest configurations in molecular detail.

Regulation of vascular remodeling by immune microenvironment after the establishment of autologous arteriovenous fistula in ESRD patients.

Autogenous arteriovenous fistula (AVF) is the preferred dialysis access for receiving hemodialysis treatment in end-stage renal disease patients. After AVF is established, vascular remodeling occurs in order to adapt to hemodynamic changes. Uremia toxins, surgical injury, blood flow changes and other factors can induce inflammatory response, immune microenvironment changes, and play an important role in the maintenance of AVF vascular remodeling. This process involves the infiltration of pro-inflammatory and anti-inflammatory immune cells and the secretion of cytokines. Pro-inflammatory and anti-inflammatory immune cells include neutrophil (NEUT), dendritic cell (DC), T lymphocyte, macrophage (Mφ), etc. This article reviews the latest research progress and focuses on the role of immune microenvironment changes in vascular remodeling of AVF, in order to provide a new theoretical basis for the prevention and treatment of AVF failure.

Structures and growth pathways of AunCln+3- (n ≤ 7) cluster anions.

Gold chloride clusters play an important role in catalysis and materials chemistry. Due to the diversity of their species and isomers, there is still a dearth of structural studies at the molecular level. In this work, anions of AunCln+3 - and AunCln+5 - (n = 2-4) clusters were obtained by laser desorption/ionization mass spectrometry (LDI MS), and the most stable isomers of AunCln+3 - were determined after a thorough search and optimization at the TPSSh/aug-cc-pVTZ/ECP60MDF level. The results indicate that all isomers with the lowest energy have a planar zigzag skeleton. In each species, there is one Au(III) atom at the edge connected with four Cl atoms, which sets it from the other Au(I) atoms. Four growth pathways for AunCln+3 - (n = 2-7) clusters are proposed (labelled R1, R2, R3 and R4). They are all associated with an aurophilic contact and are exothermic. The binding energies tend to stabilize at ∼ -41 kcal/mol when the size of the cluster increases in all pathways. The pathway R1, which connects all the most stable isomers of the respective clusters, is characterized by cluster growth due to aurophilic interactions at the terminal atom of Au(I) in the zigzag chains. In the pathway of R4 involving Au-Au bonding in its initial structures (n ≤ 3), the distance between intermediate gold atoms grows with cluster size, ultimately resulting in the transfer of the intermediate Au-Au bonding into aurophilic interaction. The size effect on the structure and aurophilic interactions of these clusters will be better understood based on these discoveries, potentially providing new insights into the active but elusive chemical species involved in the corresponding catalytic reactions or nanoparticle synthesis processes.

New-onset atrial fibrillation following arteriovenous fistula increases adverse clinical events in dialysis patients with end-stage renal disease.

Background: End-stage renal disease (ESRD) patients have a high potential cardiovascular burden, and cardiovascular disease (CVD) is the leading cause of death in maintenance haemodialysis (MHD) patients. Arteriovenous fistula (AVF) is the preferred vascular access for MHD patients, but AVF significantly affects the haemodynamics of the cardiovascular system, leading to or exacerbating CVD, including atrial fibrillation (AF). This study aimed to evaluate the impact of AVF on cardiac function, especially of the left atrium (LA), in patients with ESRD and to further explore the relationship between AVF establishment and the occurrence of AF. Methods: We selected 1,107 ESRD patients on haemodialysis using AVF and 550 patients with tunneled-cuffed catheters (TCC) admitted between January 2016 and December 2022 for follow-up to compare the rate of AF between the two groups. A total of 153 patients in the AVF group with complete information (clinical data, echocardiographic and biochemical indices, and other data) were enrolled and retrospectively analysed for risk factors for the development of AF and were followed up for adverse clinical outcomes (including all-cause death, cardiac death, readmission due to heart failure, and stroke). Results: The incidence of new-onset AF was higher in the AVF group than the TCC group after dialysis access was established (16.30% vs. 5.08%, P < 0.001). Echocardiography showed that the LA anteroposterior diameter increased (P < 0.001) and the incidence of AF increased from 11.76% to 26.14% (P = 0.001) after AVF establishment. Multivariate logistic regression analysis showed that age and LA enlargement were independent risk factors for new-onset AF after AVF establishment (P < 0.05). Adverse clinical outcomes were more common in patients with AF than in patients without AF (P < 0.001). Multivariate Cox risk regression analysis suggested that new-onset AF (HR = 4.08, 95% CI: 2.00-8.34, P < 0.001) and left ventricular systolic dysfunction (HR = 2.42, 95% CI: 1.20-4.88, P = 0.01) after AVF establishment were independent risk factors for adverse clinical outcomes. Conclusion: LA enlargement after AVF establishment is associated with a significant increase in the incidence of AF, in addition, AF which is as an important influential factor in patients with MHD combined other systemic diseases might increase adverse clinical events. Clinical Trial Registration: (NCT06199609).

The Distribution of Cervical Human Papillomavirus Infection Among Chinese Adult Women.

Background: The characteristics and genotypic distribution of human papillomavirus (HPV) infection differ in different countries and regions. The purpose of this study was to analyze the distribution of 27 HPV subtypes among adult women receiving health examinations in Jinan, China. Methods: A retrospective analysis was performed to analyze HPV subtype infection among adult women who underwent cervical cancer screening from January 1, 2020, to December 31, 2020. Results: Among 4746 women receiving HPV testing, 682 cases were positive, representing 14.4% of patients. In total, 514 cases were infected by a single HPV subtype (75.4%), 115 cases had dual infections (16.9%), and 53 cases had multiple infections (7.7%). Among the 682 cases of HPV infection, 503 cases (73.8%) were high-risk HPV infections. The most common high-risk HPV strains were HPV 52 (23.3%), HPV 16 (13.5%), and HPV 58 (12.7%). Low-risk HPV strains infected 179 cases (26.2%). The most common genotypes were HPV 61 (25.7%), HPV 81 (21.2%), and HPV 55 (15.6%). Conclusion: The HPV infection rate in healthy women was high, and the mixed infection rate was as high as 24.6%, highlighting the need for increased attention to this virus.

The RADAR technique in reconstruction of failed autologous arteriovenous fistulas due to juxta-anastomotic stenosis is equivalent to that with traditional surgery in maintenance hemodialysis patients.

OBJECTIVE: Autologous arteriovenous fistula (AVF) is recommended as superior vascular access for hemodialysis but has a high rate of failure, and juxta-anastomotic stenosis (JAS) is one of the predominant causes of fistula failure. The aim of this study was to compare the primary patency in reconstruction of failed AVFs due to JAS between the radial artery deviation and reimplantation (RADAR) technique and traditional surgery (end-vein to side-artery neo-anastomosis) in maintenance hemodialysis (MHD) patients. METHODS: A total of 1215 MHD patients with failed AVF were enrolled in this retrospective cohort study, and 614 patients with failed AVF received surgical intervention. Among these surgical interventions, 417 patients experienced AVF failure due to JAS. Finally, 25 patients who received the RADAR technique were enrolled. Controls of 50 patients received traditional surgery were randomly selected matched by age and sex. Clinical data such as age, sex, comorbidities, and blood biochemical indices were collected. Kaplan-Meier survival curves and Cox proportional hazards analyses were used to explore the difference between the RADAR group and the traditional group in reconstruction of failed AVFs. RESULTS: The RADAR group and the traditional group shared common baseline characteristics. The primary patencies of the reconstructed AVFs were 88.8%, 79.0%, 72.2%, 57.4%, and 38.3% at 12, 24, 36, 48, and 60 months among the 75 patients, respectively. Kaplan-Meier survival curve analysis demonstrated similar primary patencies in the two groups (log-rank test, p = 0.73). Compared with the traditional group, the RADAR group had no difference in predicting AVF failure after adjusting for potential confounders, with an HR of 0.92 (95% CI, 0.18-4.63). CONCLUSIONS: The primary patency of the RADAR technique and the traditional surgery in the reconstruction of failed AVFs due to JAS is almost equal in 5 years.

Structural Characterization of the Metalized Radical Cations of Adenosine ([Ade+Li-H]•+ and [Ade+Na-H]•+) by Infrared Multiphoton Dissociation Spectroscopy and Theoretical Studies.

Nucleoside radicals are key intermediates in the process of DNA damage, and alkali metal ions are a common group of ions in living organisms. However, so far, there has been a significant lack of research on the structural effects of alkali metal ions on nucleoside free radicals. In this study, we report a new method for generating metalized nucleoside radical cations in the gas phase. The radical cations [Ade+M-H]•+ (M = Li, Na) are generated by the 280 nm ultraviolet photodissociation (UVPD) of the precursor ions of lithiated and sodiated ions of 2-iodoadenine in a Fourier transform ion cyclotron resonance (FT ICR) cell. Further infrared multiphoton dissociation (IRMPD) spectra of both radical cations were recorded in the region of 2750-3750 cm-1. By combining these results with theoretical calculations, the most stable isomers of both radicals can be identified, which share the common characteristics of triple coordination patterns of the metal ions. For both radical species, the lowest-energy isomers undergo hydrogen transfer. Although the sugar ring in the most stable isomer of [Ade+Li-H]•+ is in a (South, syn) conformation similar to that of [Ado+Na]+, [Ade+Na-H]•+ is distinguished by the unexpected opening of the sugar ring. Their theoretical spectra are in good agreement with experimental spectra. However, due to the flexibility of the structures and the complexity of their potential energy surfaces, the hydrogen transfer pathways still need to be further studied. Considering that the free radicals formed directly after C-I cleavage have some similar spectral characteristics, the existence of these corresponding isomers cannot be ruled out. The findings imply that the structures of nucleoside radicals may be significantly influenced by the attached alkali metal ions. More detailed experiments and theoretical calculations are still crucial.

Distinguishing gas phase lactose and lactulose complexed with sodiated L-arginine by IRMPD spectroscopy and DFT calculations.

We present the origin of the observed differentiation of lactose and lactulose achieved by complexation with sodiated L-arginine (ArgNa+). We find that the infrared multiphoton dissociation (IRMPD) bands in 3600-3650 and >3650 cm-1 regimes for gas phase lactose and lactulose, respectively, vanish when forming host-guest complexes with ArgNa+. We interpret these differences in the IRMPD spectra by scrutinizing the interactions between the functional groups (guanidium, -CO2-Na+) in ArgNa+ and -OHs in lactose/lactulose. Our calculated structures and infrared spectra of lactose/ArgNa+ and lactulose/ArgNa+ host-guest pairs indicate that the functional groups interact with the low- and high-frequency -OH stretch modes of lactose and lactulose, respectively, in the 3600-3720 cm-1 window.

Structural Diversity of Protonated Citric Acid-Ammonia Clusters and Its Atmospheric Implication.

Various acid-base molecular clusters involving organic species can serve as precursors that play important roles in the formation of an atmospheric aerosol. Due to its structural flexibility and its ability to form multiple hydrogen bonds, citric acid acts as a key species in forming clusters that are critical in the nucleation of related aerosol precursors. Thus, it is provoking to characterize the structures of these clusters at the molecular level. In this paper, protonated citric acid-ammonia clusters of various sizes were generated by electrospray ionization and studied by tandem mass spectrometry. The structures of [(CA)2+NH4]1+ and [(CA)4+NH4]1+ were further characterized by the method of infrared photodissociation (IRPD) spectroscopy. Combined with theoretical calculations, it is found that the most stable structures of the dimeric and tetrameric isomers show the shapes of an ingot and a lantern, respectively. It has been revealed that the temperature has a great effect on the contributions of different isomers for both dimers and tetramers. The dominat isomers are found to have more open structures at higher temperatures, facilitating the growth of clusters through new hydrogen bonds.

Selective confinement of potassium, rubidium, or caesium ions in a non-covalent hydroxyproline octamer cage stabilized by cis-hydroxyl locks.

While numerous studies have focused on the impact of chirality on some magic amino acid clusters, this article investigates the effects of steric isomerization using 4-hydroxyproline octamers as a model system. Through mass spectrometry, infrared photodissociation spectroscopy, and theoretical calculation, it was demonstrated that the cis-4-hydroxy-L-proline octamer can selectively cage potassium, rubidium, or caesium ions through stable cis-hydroxyl locks, while the trans-form cannot. The results highlight the importance of hydroxyl group orientation in designing biocompatible membrane transporters with high ion-selectivity.

Capture of small clusters by ligand-solvent interaction.

Clusters are considered to become increasingly significant for elaborating the nanocrystal's formation mechanism. However, capturing the clusters with high chemical potential is challenging because of the lack of effective strategies. In this work, the key role of ligand-solvent interaction has been revealed for the stabilization of clusters in silver telluride synthesis. The Flory interaction coefficient that comprehensively regards the temperature and dispersion, polarity, and hydrogen bonding of the solvent has been used to evaluate the ligand-solvent interaction and thus assist in the design of synthetic systems. Small silver telluride clusters have been successfully captured, and the composition of the smallest cluster is determined as Ag7Te8(SCy)2 (SCy represents the ligand). This work provides new insights into the design of cluster/nanocrystal synthesis systems and paves the way to revealing the mechanism of precursor-cluster-nanocrystal conversion.

Treatment with imatinib was useful to delay the neointimal hyperplasia of aortocaval fistula in adenine-induced renal failure rats.

PURPOSE: The study was conducted to investigate the effect of the treatment with imatinib, a c-kit specific inhibitor, on the neointimal hyperplasia (NIH) of aortocaval fistula (ACF) in adenine-induced renal failure rats. MATERIALS AND METHODS: All rats were randomly assigned to 4 groups: rats were fed on a normal diet (normal group); rats were fed on a 0.75% adenine-rich diet (renal failure group). The remaining rats underwent ACF after receiving a 0.75% adenine-rich diet and received daily saline gavage (model group) or imatinib gavage (imatinib group) for 7 days after surgery. Immunohistochemical method was used to detect c-kit expression, and Elastomeric Verhoeff-Van Gieson (EVG) staining was used to observe morphological changes of the ACF. The Pearson correlation analysis was used to evaluate the correlations of c-kit expression with intimal thickness and the percentage of stenosis, respectively. RESULTS: The renal failure group showed positive c-kit expression on the intima of the inferior vena cava (IVC), whereas the normal group did not. Compared to the model group, intimal thickness (P = 0.001), the percentage of stenosis (P = 0.006) and c-kit expression (P = 0.04) were decreased in the imatinib group at 8 weeks postoperatively. C-kit expression was positively correlated with both intimal thickness and percentage of stenosis (intimal thickness: R = 0.650, P = 0.003; the percentage of stenosis: R = 0.581, P = 0.011) in both the model and imatinib groups. CONCLUSION: Treatment with imatinib, a c-kit specific inhibitor, was useful to delay the NIH of ACF in adenine-induced renal failure rats.

Vascular calcification in CKD: New insights into its mechanisms.

Vascular calcification (VC) is a common complication of chronic kidney disease (CKD) and contributes to an increased risk of cardiovascular morbidity and mortality. However, effective therapies are still unavailable at present. It has been well established that VC associated with CKD is not a passive process of calcium phosphate deposition, but an actively regulated and cell-mediated process that shares many similarities with bone formation. Additionally, numerous studies have suggested that CKD patients have specific risk factors and contributors to the development of VC, such as hyperphosphatemia, uremic toxins, oxidative stress and inflammation. Although research efforts in the past decade have greatly improved our knowledge of the multiple factors and mechanisms involved in CKD-related VC, many questions remain unanswered. Moreover, studies from the past decade have demonstrated that epigenetic modifications abnormalities, such as DNA methylation, histone modifications and noncoding RNAs, play an important role in the regulation of VC. This review seeks to provide an overview of the pathophysiological and molecular mechanisms of VC associated with CKD, mainly focusing on the involvement of epigenetic modifications in the initiation and progression of uremic VC, with the aim to develop promising therapies for CKD-related cardiovascular events in the future.

Structure and bonding properties of the platinum-mediated tetrametallic endohedral fullerene La3Pt@C98.

Nowadays, focus is on encapsulating a greater variety and amount of metal species into fullerene cages due to their diverse structures and fascinating properties. Nevertheless, the encapsulation of more positively charged metal atoms inside one cage means more Coulomb repulsion, which makes the formation of such endohedral metallofullerenes (EMFs) difficult. In general, non-metallic atoms such as N and O should be introduced as mediators for the formation of trimetallic or tetrametallic endohedral fullerenes. However, it is still unknown whether metal atoms can serve as mediators themselves to form such EMFs. In this paper, the endohedral tetrametallic fullerene La3Pt@C98 with the platinum atom as a metallic mediator is reported. The EMFs of La3Pt@C2n (2n = 98-300) were generated by the method of laser ablation in the gas phase and verified by mass spectrometry. Among them, the EMF of La3Pt@C98 was selected and studied by theoretical calculations. Results show that the two most stable isomers are La3Pt@C2(231010)-C98 and La3Pt@C1(231005)-C98. For both of them, the inner La3Pt metallic cluster appears in a pyramidal shape, different from the planar triangular pattern of La3N clusters previously reported. Further calculations prove the existence of encaged La-Pt bonds in the La3Pt cluster. It was also revealed that the negatively charged Pt atom is situated near the center of the four-center two-electron (4c-2e) metal bond with the highest occupancy number. The platinum-mediated cluster stabilizes the EMFs greatly, promising the possibility of synthesizing new species of Pt-containing EMFs.

Simultaneous quantitative chiral analysis of four isomers by ultraviolet photodissociation mass spectrometry and artificial neural network.

Although mass spectrometry (MS) has its unique advantages in speed, specificity and sensitivity, its application in quantitative chiral analysis aimed to determine the proportions of multiple chiral isomers is still a challenge. Herein, we present an artificial neural network (ANN) based approach for quantitatively analyzing multiple chiral isomers from their ultraviolet photodissociation mass spectra. Tripeptide of GYG and iodo-L-tyrosine have been applied as chiral references to fulfill the relative quantitative analysis of four chiral isomers of two dipeptides of L/D His L/D Ala and L/D Asp L/D Phe, respectively. The results show that the network can be well-trained with limited sets, and have a good performance in testing sets. This study shows the potential of the new method in rapid quantitative chiral analysis aimed at practical applications, with much room for improvement in the near future, including selecting better chiral references and improving machine learning methods.

K+-Selectivity Due to Coordination with a D4d-Symmetric Homochiral Proline Octamer Verified by Mass Spectrometry and Infrared Photodissociation Spectroscopy.

Both phenomena of homochirality and sodium-potassium ion selectivity in cells have been regarded as important issues in the process of the origin of life. However, whether K+/Na+ selectivity was involved in homochirogenesis has never been considered. Herein, we report that a homochiral proline octamer shows high K+-selectivity. Coordination of K+ results in formation of a stable, noncovalent, D4d-symmetric complex, as demonstrated by mass spectrometry, infrared photodissociation spectroscopy, and calculations. A cooperative relationship between an eight-coordinated metal cation and a homochirality-restricted topological hydrogen-bonded proline network is the key for the K+/Na+ selectivity. As the complex comprises merely the basic chiral amino acid, it provides a possible linkage between K+/Na+ selectivity and the origin of chirality on the prebiotic Earth.

Identifying a selective oligopeptide clamp in the gas phase.

Oligopeptide foldamers are promising as minimalist functional analogues to proteins. Herein, we report a versatile and cost-effective experimental scheme in the gas phase that can facilely identify selective oligopeptides and unambiguously resolve the corresponding folding conformations. Based on this methodology, a stereoselective oligopeptide clamp targeting ß2-blockers is successfully identified.

Elevated c-kit expression in failed autologous arteriovenous fistulas in end-stage renal disease patients.

BACKGROUND: Serum stem cell factor is elevated in end-stage renal disease (ESRD) patients. This study aimed to investigate the expression of the c-kit receptor, which is the specific membrane receptor of stem cell factor, in failed autologous arteriovenous fistulas (AVFs) in end-stage renal disease patients. METHODS: A total of 14 ESRD patients with initial AVFs creation and 16 ESRD patients with reconstruction were enrolled in this study. Hematoxylin and eosin (H&E) and elastic Verhoeff-Van Gieson (EVG) staining were used for histomorphometric analyses. Immunohistochemistry was used to examine the expression of c-kit in the intima, and a correlation analysis was performed with the intimal area and the percentage of area stenosis. A double-label immunofluorescence method was used to explore the colocalization of c-kit with α-smooth muscle actin (α-SMA) and CD31. The expression of c-kit and the related PI3K/Akt signaling axis, including PI3K, P-PI3K, Akt, P-Akt473, P-Akt308, and mTOR, was measured by western blotting. RESULTS: Internal elastic lamina (IEL) area, intimal area, percentage of area stenosis, and average optical density (AOD) of c-kit in the intima were significantly higher in the failed group than in the preoperative group (p ⩽ 0.001). The AOD of c-kit in the intima was positively correlated with the intimal area and the percentage of stenosis (intimal area: R = 0.744, p < 0.001; the percentage of stenosis: R = 0.923, p < 0.001). C-kit colocalized with α-SMA but not with CD31 in studies of c-kit target cells. Moreover, the levels of c-kit and P-PI3K, P-Akt473 and mTOR in the PI3K/Akt axis were also higher in the failed group than in the initial group (p < 0.05). CONCLUSIONS: C-kit and related proteins associated with the PI3K/Akt pathway were elevated in failed AVFs among ESRD patients and that the expression level of c-kit in the intima correlates with the degree of AVF stenosis.

Drug in Drug: A Host-Guest Formulation of Azocalixarene with Hydroxychloroquine for Synergistic Anti-Inflammation.

Macrocyclic delivery and therapeutics are two significant topics in supramolecular biomedicine. The functional integration of these topics would open new avenues for treating diseases synergistically. However, these two individual topics have only been occasionally merged, probably because of the lack of functionalized design of macrocyclic host and the lack of efficient recognition between host and guest drugs. Herein, a "drug-in-drug" strategy is proposed, in which an active drug is encapsulated by a macrocycle possessing therapeutic activity to form a multifunctional supramolecular active pharmaceutical ingredient. As a proof-of-concept, a complex of hydroxychloroquine (HCQ) with sulfonated azocalix[4]arene (HCQ@SAC4A) is prepared to treat rheumatoid arthritis (RA) in a combined fashion. SAC4A is a therapeutic agent that exhibits scavenging capacity for reactive oxygen species and exerts an anti-inflammatory effect. It is also a hypoxia-responsive carrier that can deliver HCQ directly to the inflammatory articular cavity. Consequently, HCQ@SAC4A achieves the synergistic anti-inflammatory effect on both inflamed RAW 264.7 cells and RA rats. This effect is attributed to the temporal and spatial consistency of the two active ingredients of the complex. As a new paradigm for combinational therapy, the drug-in-drug strategy advances in easy preparation, mix-and-match combination, and precise ratiometric control.