Latest ArticlesThe von Hippel-Lindau tumor suppressor (VHL) has been extensively used to develop degraders targeting numerous proteins of interest. However, studies on the rational design of VHL-proteolysis-targeting chimeras (PROTACs) remain scarce. This study aimed to develop strategies to investigate VHL-recruiting PROTACs connecting with varying attachment sites on VHL ligands, which could be utilized for KRASG12C degraders development and expanded to additional targets. We developed a molecular dynamics (MD)-based strategy to explore the stability of ternary complexes induced by KRASG12C PROTACs with four distinct attachment sites of VH032. We found a potent degrader namely YN14-H, linked to hydroxyl group on VH032 benzene ring, exhibited the most superior ability of inducing ternary complexes, reflected by the lowest dissociation constant (Kd) for ternary complex induction and the highest AlphaScreen (AS)-based interaction. YN14-H inhibited cell growth with low nanomolar half maximal inhibitory concentration (IC50) and half maximal degradation concentration (DC50) values as well as >98% of maximum degradation (Dmax) in NCI-H358 and MIA PaCa-2 cells harboring KRASG12C-mutation. Mechanistically, YN14-H significantly induced apoptosis and inhibited the migratory capacity. Notably, YN14-H demonstrated favorable pharmacokinetic properties and excellent antitumor activity in vivo. Furthermore, bromodomain-containing protein 7 (BRD7) and Bruton tyrosine kinase (BTK) degraders attached to distinct sites on VH032 further verified the rationality and universality of our MD-based strategies. Our findings demonstrated that YN14-H could serve as a promising candidate for the treatment of tumors with KRASG12C-mutation and present a strategy for the rational design of VHL-recruiting PROTACs that target additional proteins at distinct attachment sites.
The protein corona formation has been reported to influence the liposomes’ behavioral performance in vivo. Accordingly, the effect of physiologically relevant inorganic ion pairs (sodium chloride, sodium sulfate, magnesium chloride, and magnesium sulfate) was investigated. Bovine serum albumin (BSA) was selected as the model protein. Parameters including particle size and zeta potential were assessed, while various spectroscopic techniques were utilized to elucidate the changes in BSA during its interaction with liposomes. The particle size and light intensity distribution changes indicated that the introduction of inorganic pairs, especially the metal cations, could significantly influence both the adsorption of BSA and the aggregation of particles. Furthermore, spectral characterization elucidated that BSA exhibited more extended peptide chains with enhanced exposure to hydrophobic acid amino residues upon adding ion pairs. Electrostatic adsorption and chelation insertion were proposed as metal ion binding modes and the corresponding BSA corona formation. In the electrostatic adsorption mode, sodium ions can enhance the electrostatic interactions, facilitating the “connection” between BSA and liposomes. Magnesium ions can induce stronger hydrophobic interactions through chelation, effectively “drag” BSA segments into the lipid bilayer. This work highlighted important physiological factors for protein-liposome interaction and provided rational model constructions to lay the foundation for further relevant studies.
Hemorrhagic shock (HS) is a leading cause of death worldwide, particularly within the first 24 h post-injury. Current treatments are limited, especially in low-resource settings. Therapeutic hypothermia (TH) offers potential benefits by reducing metabolic demands and protecting organs, but its application in HS is challenged by cooling difficulties and side effects. This study introduces a novel nasal gel formulation of N6-cyclohexyladenosine (CHA), an adenosine A1 receptor agonist, designed to enhance brain delivery while minimizing peripheral side effects. In a mouse model of HS, administration of CHA nasal gel significantly improved survival rates, reduced metabolic rates, and protected major organs without worsening coagulopathy. Metabolomics analysis revealed a shift towards fatty acid oxidation and increased antioxidant capacity. These findings demonstrate that CHA nasal gel effectively induces TH, offering a safe and innovative treatment strategy for HS, particularly in resource-limited environments.
Thermoplastic polyurethane (TPU) consists of a hard segment and a soft segment, where the former affords mechanical strength and thermal stability, while the latter provides a possibility of good ionic conductivity by promoting dissociation of ions from the lithium salt. Thus, TPU attracts a wide interest recently as a promising polymer electrolyte for solid-state lithium batteries. However, the relatively low ionic conductivity of TPU still restricts its actual applications due to the aggregation of polymer chains, which greatly reduces the dissociation of lithium salts. Herein, a strategy to address this challenge was adopted by in situ polymerization poly(ethylene glycol diacrylate) (PEGDA) in fully dispersed TPU. Hence a stretchable solid-state electrolyte (denoted as TELL and the contrast sample was denoted as TLL) with high ionic conductivity of 7.18 × 10−4 S/cm was obtained at room temperature. The Li+ transference number is 0.85 in Li|TELL|Li cell and can stably undergo charge-discharge cycles for 1400 h at a current density of 0.1 mA/cm2, while the contrast sample is short-circuited after 634 h of cycling. The LiFePO4|TELL|Li cell achieves a capacity retention of 78.93% after 200 cycles at 2 C. The LiFePO4|TLL|Li cell only gains the capacity retention of 51.9% after 50 cycles at the same current density. So, the method adopted here may provide a new approach to realize a flexible solid-state electrolyte with high ion-conductivity.
In situ tumor vaccines, which leverage the antigenic profile of individual tumors, have demonstrated significant potential in tumor immunotherapy. However, their efficacy is often limited by the immunosuppressive tumor microenvironment (TME) and insufficient tumor targeting. To address these challenges, we engineered in situ nanovaccines through the self-assembly of the photosensitizer indocyanine green, immune adjuvant aluminum (Al3+), and hydrophilic drug zoledronic acid (ZOL). Intravenous injection of these nanovaccines led to efficient tumor accumulation, enhancing drug bioavailability and enabling the release of tumor-associated antigens via photothermal therapy. Additionally, the built-in ZOL induces polarization of tumor-associated macrophages, reversing the immunosuppressive TME. The potent antitumor immune response triggered by these nanovaccines effectively suppresses tumor growth. This study, which integrates a straightforward assembly method, substantial drug loading capacity, and promising therapeutic outcomes, introduces a novel and effective paradigm for carrier-free in situ nanovaccines in cancer treatment.
Pulmonary diseases have long posed a severe threat to human life and health. The incidence and mortality rates of pulmonary diseases have shown a rising trend year by year, highlighting the urgency of developing safe and effective therapeutic approaches. In recent years, to address the challenges faced by traditional treatment strategies for pulmonary diseases, the interdisciplinary integration has greatly promoted the rapid development of biomedical polymer materials in the field of pulmonary disease treatment. This review provides a detailed description of the structural characteristics of lung tissue, types of pulmonary diseases, traditional treatment methods, the categories and properties of biomedical polymer materials applied to pulmonary diseases. We systematically elaborate on the applications of biomedical polymer materials in the treatment of different pulmonary diseases and thoroughly discuss their functional roles in pulmonary diseases, particularly in the delivery of therapeutic agents to diseased sites, the formation of pulmonary aerosol formulations, and the facilitation of the effective accumulation of therapeutic agents. The latest research progresses of biomedical polymer materials are also introduced in pulmonary disease treatment. We have highlighted the current challenges and development opportunities of biomedical polymer materials in the treatment of pulmonary diseases, and provide future research directions for biomedical polymer materials in this field. This review will provide valuable reference for the basic research and clinical application of biomedical polymer materials in pulmonary disease treatment.
Hyperactivation of DNA repairing pathway is highly associated with the chemosensitivity and chemoresistance of cancer cells. In this manuscript, guided by cascaded one strain many compounds-global natural products social molecular networking (OSMAC-GNPS) strategy, a pair of epimeric environmental-induced metabolites were isolated from Aspergillus sp. EGF 15-0-3. Structurally, sterpiperazines A (1) and B (2) represent the first steroid-based indole alkaloids with unprecedented backbones. Biologically, compound 1 could be identified as a novel tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibitor with a unique mechanism distinct from the reported modulators, and was able to significantly enhance the sensitivity of NCI-H460 cells to the clinic chemotherapeutic drug through inhibiting the DNA repairment and enhanced the DNA damage of cancer cells.
Novel antibacterial strategies such as antibacterial photodynamic therapy (aPDT) and photothermal therapy (PTT) have gained significant attention, however, relying on a single-treatment approach still faces challenges of insufficient therapeutic efficiency and the potential for drug resistance. In this study, a multimodal synergistic antibacterial nanoplatform by coupling a carbon monoxide (CO) donor (4-(3-hydroxy-4-oxo-4H-chromen-2-yl)benzoic acid (4-BA)) with carbon dots (CDs) is developed, referred to as CDs-CO, which integrates multiple antibacterial modes of aPDT, PTT, and gas therapy. This nanoplatform is designed for highly efficient antibacterial action with a low risk of inducing drug resistance. CDs are engineered to possess tailored functions, including deep-red light-triggered heat and singlet oxygen (1O2) production. After modification with 4-BA and exposure to 660 nm laser irradiation, CDs-CO exhibits favorable photothermal conversion efficiency (η = 52.7%), robust 1O2 generation, and 1O2-activated CO release. Antibacterial experiments demonstrated the excellent sterilization effects of CDs-CO against both Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), underscoring the enhanced antibacterial efficiency of this multimodal nanoplatform. This study offers a rational approach for designing multimodal synergistic antibacterial platforms, highlighting their potential for effectively treating bacterial infections.
Achieving rational control over polarization states and color of circularly polarized luminescence (CPL) through simple modulation poses a challenging yet highly practical problem. To address this issue, we developed a mechano-responsive chiral supramolecular system based on a cyclohexanediamide-derived gelator CCPy. This molecule exhibited a strong blue fluorescence accompanied by a distinct CPL signal upon forming a supramolecular gel in toluene. However, upon the application of mechanical force, the gel rapidly transformed into a faintly emissive suspension with a silent CPL signal, along with a notable morphological alteration. Furthermore, by implementing the circularly polarized Förster resonance energy transfer (CP-FRET) strategy, the mechano-responsiveness was effectively imparted to binary systems through the incorporation of dyes Nile red (NR) and coumarin 7 (C7), thus realizing mechanical force-switchable green and red CPL systems. It was particularly noteworthy that by adjusting the ratio of CCPy, C7 and NR, a ternary mechanical force-induced CPL ON-OFF switch that emitted a standard white emission was achieved through sequential CP-FRET. Following this, an information encryption experiment was performed. This work provided a paradigm for fabricating smart multi-color and white-light CPL materials.
Photoreforming poly(lactic acid) (PLA) plastics into pyruvic acid (PA) coupled with hydrogen evolution is of great significance for sustainable development. However, a significant challenge lies in α-OH bond cleaving of lactic acid (LA). Herein, CdS/Bi4Ti3O12 composite is fabricated, bridged by Bi−S bonds, through in-situ growth of CdS nanoparticles on Bi4Ti3O12 nanoflowers for the successive removal of hydrogen from α-C in LA. In-situ X-ray photoelectron spectroscopy confirms the S-scheme carriers transfer route and interfacial Bi−S bond in CdS/Bi4Ti3O12. Consequently, the photo-electrons and holes with extended lifetimes and strong redox potential accumulate in the CdS conduction band and Bi4Ti3O12 valence band, respectively, as evidenced by in-situ electron spin resonance and time-resolved photoluminescence. This facilitates the generation of •OH radicals, which further participate in the successive dehydrogenation reaction of LA. Consequently, the photoreforming efficiencies of converting PLA into PA and H2 by CdS/Bi4Ti3O12 are 1.7 and 3.16 mmol g–1 h–1, which are respectively 2.8 and 22 times higher than that by pristine Bi4Ti3O12. The present work provides a new approach for designing S-scheme to achieve hydrogen production and value-added conversion of plastics.
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