Wei Huang

The introduction of weakly solvating additives (WSAs) into aqueous electrolytes holds significant potential in promoting the desolvation kinetics of Zn2+ and reducing polarization. However, the current strategy of WSA screening primarily depends on trial-and-error experiments and theoretical calculations. This study reveals that, among various molecular features, the electrostatic potential minimum (ESPmin) exhibits the strongest correlation with the desolvation activation energy (Ea), demonstrating that ESPmin could serve as an effective descriptor for screening WSAs. Herein, we propose a data-driven screening strategy based on ESPmin, in which ESPmin can be accurately predicted directly from molecular structure using a graph convolutional neural network (GCN) model. Assisted by this strategy, several promising WSAs, including tetrahydropyran, methanol, and acetone, were successfully identified. As a proof of concept, tetrahydropyran was selected as the additive for systematic studies. Remarkably enhanced cycling stability with a lifespan of over 2400 h and low overpotential was demonstrated for the symmetric cell with tetrahydropyran. The proposed data-driven strategy enables the rapid screening of WSAs directly from molecular structures, offering an efficient pathway for the exploration of high-performance electrolyte additives.

Aryl fluorosulfate warheads, possessing sulfur(VI) fluoride exchange (SuFEx) reaction, hold significant promise for the development of covalent protein drugs. However, their SuFEx reactivity remains limited within the complex microenvironment of protein interactions. To address this challenge, we sought to enhance their reactivity by adjusting the electronic and steric properties of warheads. Herein, we synthesized various maleimide‐functionalized aryl fluorosulfate (MFS) bearing different substituents (e.g., o‐F, o‐CF ₃ , o‐NO ₂ , o‐CH ₃ , o‐OCH ₃ , o‐Cl, o‐Br, o‐I, 2,6‐diF, and m‐F), which were then chemically conjugated to Adnectin (an EGFR‐targeting protein). The SuFEx reactivity of the resulting xMFS‐modified Adnectin was systematically investigated by comparing their covalent cross‐linking efficiency to EGFR. Notably, the meta‐Fluoro‐substituted MFS warhead, featuring moderate electrophilicity and minimal steric hindrance, exhibited the highest reactivity, achieving a 3.5‐fold increase in cross‐linking efficiency compared to unsubstituted control. The m‐F MFS‐modified Adnectin was further attached to the surface of albumin‐bound DXd. Leveraging its enhanced SuFEx reactivity, the resulting covalent albumin‐bound drug exhibited 6.4‐fold higher intracellular accumulation, 3.0‐fold greater tumor retention, and 4.0‐fold higher antitumor efficiency compared to unsubstituted control. Overall, fine‐adjusting the electronic and steric properties of warheads significantly enhances their SuFEx reactivity, enabling the rational design of SuFEx‐based warheads and facilitating the application in covalent protein drugs.

Aryl fluorosulfate warheads, possessing sulfur(VI) fluoride exchange (SuFEx) reaction, hold significant promise for the development of covalent protein drugs. However, their SuFEx reactivity remains limited within the complex microenvironment of protein interactions. To address this challenge, we sought to enhance their reactivity by adjusting the electronic and steric properties of warheads. Herein, we synthesized various maleimide‐functionalized aryl fluorosulfate (MFS) bearing different substituents (e.g., o‐F, o‐CF ₃ , o‐NO ₂ , o‐CH ₃ , o‐OCH ₃ , o‐Cl, o‐Br, o‐I, 2,6‐diF, and m‐F), which were then chemically conjugated to Adnectin (an EGFR‐targeting protein). The SuFEx reactivity of the resulting xMFS‐modified Adnectin was systematically investigated by comparing their covalent cross‐linking efficiency to EGFR. Notably, the meta‐Fluoro‐substituted MFS warhead, featuring moderate electrophilicity and minimal steric hindrance, exhibited the highest reactivity, achieving a 3.5‐fold increase in cross‐linking efficiency compared to unsubstituted control. The m‐F MFS‐modified Adnectin was further attached to the surface of albumin‐bound DXd. Leveraging its enhanced SuFEx reactivity, the resulting covalent albumin‐bound drug exhibited 6.4‐fold higher intracellular accumulation, 3.0‐fold greater tumor retention, and 4.0‐fold higher antitumor efficiency compared to unsubstituted control. Overall, fine‐adjusting the electronic and steric properties of warheads significantly enhances their SuFEx reactivity, enabling the rational design of SuFEx‐based warheads and facilitating the application in covalent protein drugs.

A smart P-gp inhibitor-drug conjugate nanomedicine (Zos-SS-DTX-AI@DSPE-PEG _2k NPs) was developed to overcome multidrug resistance in breast cancer therapy, achieving enhanced therapeutic efficacy and biosafety.

The charge-reversal prodrug PIX-DMMA, activated by tumor acidity, enhances cellular uptake and anticancer efficacy while reducing systemic toxicity.

Multidrug resistance (MDR) is a significant factor contributing to chemotherapy failure in the clinical treatment of nonsmall cell lung cancer (NSCLC). The combination of P-glycoprotein (P-gp) inhibitors with chemotherapeutic agents can effectively overcome MDR by inhibiting drug efflux from NSCLC cells. However, achieving a satisfactory therapeutic effect through the codelivery of chemotherapeutic agents and P-gp inhibitors remains challenging due to their different pharmacokinetics and physicochemical properties. In this study, we constructed a redox-responsive drug-inhibitor conjugate (CTX-SS-Zos) using cabazitaxel (CTX, a cytotoxin) and zosuquidar (Zos, a third-generation P-gp inhibitor) through a linkage containing a disulfide bond. Subsequently, this conjugate can self-assemble into uniform and stable nanoparticles (CZNPs) in the presence of DSPE-PEG_2k with a molar percentage of 10%. Administered via tail vein injection, CZNPs can accumulate at tumor sites. Upon internalization by cancer cells, the high intracellular concentration of glutathione triggers the disassembly of CZNPs and the cleavage of the redox-sensitive CTX-SS-Zos conjugate. As a result, CTX and Zos are simultaneously released, thereby reversing tumor MDR and synergistically inhibiting the growth of drug-resistant NSCLC. The in vivo tumor inhibition rate of CZNPs reaches up to 86.91% in A549/PTX tumor-bearing mice without obvious toxic side effects. These smart CZNPs may offer a promising clinical treatment approach for drug-resistant NSCLC.

Affinity proteins are multiple types of well-explored small scaffold proteins with excellent tumor targeting performance. However, due to their small size, the balance between rapid blood clearance and efficient tumor accumulation remains a challenge for their clinical application. The covalent targeting mode, endowing the affinity proteins with an irreversible binding ability to their receptor and then decoupling the pharmacodynamic effect from pharmacokinetics, may provide a promising solution for clinical applications of affinity proteins. Herein, we develop a chemical modification strategy to construct covalently targeted affinity protein drugs. Through the chemical attachment with a sulfur(VI) fluoride exchange (SuFEx) chemistry-based maleimide-substituted aryl fluorosulfate (MFS) linker, the engineered affinity protein acquires the capacity to covalently link with its targeting receptor. As a proof of concept, the MFS linker modified affibody-protein drug elicited over 72% covalent binding to the target human epidermal growth factor receptor 2 (HER2) and 185% higher cell uptake than that of the noncovalent control in vitro. In mice, the tumor retention capacity of the covalent affibody-protein drug was 2.01 times greater than that of the control group, ultimately resulting in nearly complete inhibition of tumor growth. Similar enhanced therapeutic efficacy was also obtained in another MFS linker-armed monobody-protein drug targeting the epidermal growth factor receptor (EGFR). In brief, this facile chemical modification strategy provides a general platform for preparing covalently targeted affinity protein drugs, potentially accelerating the application of protein therapeutics in diverse diseases.

Sulfur‐fluoride exchange (SuFEx) reaction is an emerging class of click chemistry reaction. Owing to its efficient reactivity under physiological conditions, SuFEx reaction is used to construct covalent protein drugs. Herein, a covalent affibody‐molecular glue drug conjugate nanoagent is reported, which can irreversibly bind with its target protein through proximity‐enabled SuFEx reaction. As a proof of concept, a latent bioreactive unnatural amino acid fluorosulfate‐L‐tyrosine (FSY) is first introduced at site 36 of the affibody with cysteine mutation (Z_HER2:342‐Cys) to produce Z_HER2:342‐36_FSY‐Cys. Subsequently, Z_HER2:342‐36_FSY‐Cys is coupled with a molecular glue drug (CR8) to yield an amphiphilic conjugate of Z_HER2:342‐36_FSY‐CR8, which can self‐assemble into affibody–drug conjugate nanoagent (Z_HER2:342‐36_FSY‐CR8 ADCN) in PBS. When Z_HER2:342‐36_FSY‐CR8 ADCN specific binds to human epidermal growth factor receptor 2 (HER2) on cancer cells, the FSY36 of Z_HER2:342 approaches to the His490 of HER2 and ultimately reacts with each other to form a covalent bond via SuFEx reaction. Such a covalent binding mode endows Z_HER2:342‐36_FSY‐CR8 ADCN with permanent binding ability to effectively increase the concentration of drugs in tumor. Eventually, the covalent Z_HER2:342‐36_FSY‐CR8 ADCN exhibits an outstanding tumor inhibition ratio of 90.03 ± 4.29% in HER2‐positive ovary tumor models, strikingly higher than that of the noncovalent one (64.25 ± 7.71%).

Cancer metastasis is responsible for more than 90% of tumor-related deaths. Especially, metastatic breast cancer (MBC) is a common malignancy with a high mortality among women worldwide. It is urgent to develop effective drugs for the treatment of MBC. Herein, biomimetic chemotherapeutic drug-gene nanoparticles (named TPT-ASO_VEGF@MM NPs) were constructed for the combination therapy of MBC. First, topotecan hydrochloride (TPT) and vascular endothelial growth factor antisense oligonucleotide (ASO_VEGF) were coself-assembled in water through electrostatic interaction to produce chemotherapeutic drug-gene nanoparticles (TPT-ASO_VEGF NPs). Then, the nanoparticles were encapsulated within macrophage membranes (MM) to form biomimetic TPT-ASO_VEGF@MM NPs with long circulation time in blood and active tumor-targeting ability. TPT-ASO_VEGF@MM NPs can be effectively internalized by breast cancer cells and then the nanoparticles collapse to simultaneously release TPT and ASO_VEGF. ASO_VEGF can inhibit the expression of VEGF, impeding the process of neovascularization and blocking the metastatic pathway of cancer cells. Meanwhile, TPT can bind to the topoisomerase I-DNA complex to prevent DNA repair and replication, and further induce apoptosis of cancer cells. In addition, TPT can also affect hypoxia-inducible factor 1α (HIF-1α) expression and inhibit hypoxia-induced tumor metastasis to achieve synergistic therapy with ASO_VEGF. In MBC mouse models, the in vivo inhibition rate of TPT-ASO_VEGF@MM NPs for lung metastasis was 89.5%, with minor toxic side effects and the least number of metastatic nodules in the lungs. In summary, TPT-ASO_VEGF@MM NPs would be a promising biomimetic nanodrug for chemo-gene combination therapy of MBC with high efficacy and safety in clinics.