J Exp Med. 2025 Sep 1;222(9):e20241454. doi: 10.1084/jem.20241454. Epub 2025 Jun 6. Membrane-IL12 adjuvant mRNA vaccine polarizes pre-effector T cells for optimized tumor control Abstract Conventional mRNA cancer vaccines can expand the quantity of tumor-specific CD8 T cells, but their effector function might be compromised. Specific cytokine signaling may enhance T cell differentiation for better tumor killing. We screened various cytokines and identified IL-12 as a potent adjuvant for mRNA vaccines, though with significant systemic toxicity. To balance efficacy and toxicity, we developed a membrane-tethered IL-12 (mtIL12) adjuvant mRNA vaccine. This design restricts mtIL12 expression to the surface of antigen-presenting cells, thereby selectively activating antigen-specific T cells without affecting bystander T or NK cells. mtIL12 adjuvant mRNA vaccination induced a unique pre-effector T cell subset that gives rise to highly responsive effector T cells, resulting in superior anti-tumor activity. Moreover, this approach overcame immune checkpoint therapy resistance and prevented cancer metastasis. Our study highlights that next-generation mRNA vaccines encoding membrane-tethered cytokine adjuvants can generate potent effector T cells, offering effective tumor control with reduced toxicity. Product: Wholesale Best Excipient For DNA/RNA Delivery,professional Excipient For DNA/RNA Delivery Suppliers

Bioact Mater. 2024 Jun 21:40:430-444. doi: 10.1016/j.bioactmat.2024.06.021. eCollection 2024 Oct. Kneadable dough-type hydrogel transforming from dynamic to rigid network to repair irregular bone defects Abstract Irregular bone defects, characterized by unpredictable size, shape, and depth, pose a major challenge to clinical treatment. Although various bone grafts are available, none can fully meet the repair needs of the defective area. Here, this study fabricates a dough-type hydrogel (DR-Net), in which the first dynamic network is generated by coordination between thiol groups and silver ions, thereby possessing kneadability to adapt to various irregular bone defects. The second rigid covalent network is formed through photocrosslinking, maintaining the osteogenic space under external forces and achieving a better match with the bone regeneration process. In vitro, an irregular alveolar bone defect is established in the fresh porcine mandible, and the dough-type hydrogel exhibits outstanding shape adaptability, perfectly matching the morphology of the bone defect. After photocuring, the storage modulus of the hydrogel increases 8.6 times, from 3.7 kPa (before irradiation) to 32 kPa (after irradiation). Furthermore, this hydrogel enables effective loading of P24 peptide, which potently accelerates bone repair in Sprague-Dawley (SD) rats with critical calvarial defects. Overall, the dough-type hydrogel with kneadability, space-maintaining capability, and osteogenic activity exhibits exceptional potential for clinical translation in treating irregular bone defects. Keywords: Dough-type hydrogel; Dynamic network; Irregular bone defect; Kneadable; Rigid network. Product: Manufacturer Of PEG Derivative By Structure,Wholesale PEG Derivative By Structure

Pharmaceutics. 2025 Jan 24;17(2):157. doi: 10.3390/pharmaceutics17020157. Engineering Lipid Nanoparticles to Enhance Intracellular Delivery of Transforming Growth Factor-Beta siRNA (siTGF-β1) via Inhalation for Improving Pulmonary Fibrosis Post-Bleomycin Challenge Abstract Background/Objectives: Transforming Growth Factor-beta (TGFβ1) plays a core role in the process of pulmonary fibrosis (PF). The progression of pulmonary fibrosis can be alleviated by siRNA-based inhibiting TGF-β1. However, the limitations of naked siRNA lead to the failure of achieving therapeutic effect. This study aimed to design lipid nanoparticles (LNPs) that can deliver siTGF-β1 to the lungs for therapeutic purposes. Methods: The cytotoxicity and transfection assay in vitro were used to screen ionizable lipids (ILs). Design of Experiments (DOE) was used to obtain novel LNPs that can enhance resistance to atomization shear forces. Meanwhile, the impact of LNPs encapsulating siTGF-β1 (siTGFβ1-LNPs) on PF was investigated. Results: When DLin-DMA-MC3 (MC3) was used as the ILs, the lipid phase ratio was MC3:DSPC:DMG-PEG2000:cholesterol = 50:10:3:37, and N/P = 3.25; the siTGFβ1-LNPs could be stably delivered to the lungs via converting the siTGFβ1-LNPs solution into an aerosol (atomization). In vitro experiments have confirmed that siTGFβ1-LNPs have high safety, high encapsulation, and can promote cellular uptake and endosomal escape. In addition, siTGFβ1-LNPs significantly reduced inflammatory infiltration and attenuated deposition of extracellular matrix (ECM) and protected the lung tissue from the toxicity of bleomycin (BLM) without causing systemic toxicity. Conclusions: The siTGFβ1-LNPs can be effectively delivered to the lungs, resulting in the silencing of TGF-β1 mRNA and the inhibition of the epithelial-mesenchymal transition pathway, thereby delaying the process of PF, which provides a new method for the treatment and intervention of PF. Keywords: design of experiments (DOE); lipid nanoparticles (LNPs); pulmonary fibrosis (PF); siRNA delivery; transforming growth factor β1 (TGF-β1). Product: Wholesale Best Excipient For DNA/RNA Delivery,professional Excipient For DNA/RNA Delivery Suppliers

Molecules. 2017 Jul 15;22(7):1190. doi: 10.3390/molecules22071190. Antiviral Lipopeptide-Cell Membrane Interaction Is Influenced by PEG Linker Length Abstract A set of lipopeptides was recently reported for their broad-spectrum antiviral activity against viruses belonging to the Paramyxoviridae family, including human parainfluenza virus type 3 and Nipah virus. Among them, the peptide with a 24-unit PEG linker connecting it to a cholesterol moiety (VG-PEG24-Chol) was found to be the best membrane fusion inhibitory peptide. Here, we evaluated the interaction of the same set of peptides with biomembrane model systems and isolated human peripheral blood mononuclear cells (PBMC). VG-PEG24-Chol showed the highest insertion rate and it was among the peptides that induced a larger change on the surface pressure of cholesterol rich membranes. This peptide also displayed a high affinity towards PBMC membranes. These data provide new information about the dynamics of peptide-membrane interactions of a specific group of antiviral peptides, known for their potential as multipotent paramyxovirus antivirals. Keywords: antiviral; cholesterol; membranes; paramyxoviruses; peptides. PEG Linker: Various Kingds And Grades Of Such Monodispersed Are Readily Avaliable| SINOPEG

J Pharm Sci. 2020 Feb;109(2):981-991.  doi: 10.1016/j.xphs.2019.10.052.  Epub 2019 Nov 2. Conjugation of Amine-Functionalized Polyesters With Dimethylcasein Using Microbial Transglutaminase Abstract Protein-polymer conjugates have been used as therapeutics because they exhibit frequently higher stability, prolonged in vivo half-life, and lower immunogenicity compared with native proteins.  The first part of this report describes the enzymatic synthesis of poly(glycerol adipate) (PGA(M)) by transesterification between glycerol and dimethyl adipate using lipase B from Candida antarctica.  PGA(M) is a hydrophilic, biodegradable but water insoluble polyester.  By acylation, PGA(M) is modified with 6-(Fmoc-amino)hexanoic acid and with hydrophilic poly(ethylene glycol) side chains (mPEG12) rendering the polymer highly water soluble.  This is followed by the removal of protecting groups, fluorenylmethyloxycarbonyl, to generate polyester with primary amine groups, namely PGA(M)-g-NH2-g-mPEG12.  1H NMR spectroscopy, FTIR spectroscopy, and gel permeation chromatography have been used to determine the chemical structure and polydispersity index of PGA(M) before and after modification.  In the second part, we discuss the microbial transglutaminase-mediated conjugation of the model protein dimethylcasein with PGA(M)-g-NH2-g-mPEG12 under mild reaction conditions.  SDS-PAGE proves the protein-polyester conjugation. Keywords: CAL-B;  amine-functionalized polyester;  enzymatic polymerization;  microbial transglutaminase (mTGase);  poly(glycerol adipate) (M);  protein-polymer conjugate.

Bioconjug Chem. 2025 Feb 19;36(2):179-189.  doi: 10.1021/acs.bioconjchem.4c00392.  Epub 2025 Jan 20. PEGylation of Dipeptide Linker Improves Therapeutic Index and Pharmacokinetics of Antibody-Drug Conjugates Abstract Hydrophobic payloads incorporated into antibody-drug conjugates (ADCs) typically are superior to hydrophilic ones in tumor penetration and "bystander killing" upon release from ADCs.  However, they are prone to aggregation and accelerated plasma clearance, which lead to reduced efficacies and increased toxicities of ADC molecules.  Shielding the hydrophobicity of payloads by incorporating polyethylene glycol (PEG) elements or sugar groups into the ADC linkers has emerged as a viable alternative to directly adopting hydrophilic payloads.  In this study, ADC linkers incorporating PEG or sugar groups were synthesized by modifying dipeptide linkers, with hydrophobic monomethyl auristatin E (MMAE) serving as an exemplary hydrophobic payload.  All drug-linkers (DLs) were conjugated to RS7, a humanized antibody targeting Trop-2, with drug-to-antibody ratio (DAR) values set at 4 or 8.  Among these, the ADC molecule RS7-DL 11, featuring a methyl-PEG24 (mPEG24) moiety as a side chain to the Valine-Lysine-PAB (VK) linker, demonstrated maximum hydrophilicity, biophysical stability, and tumor suppression, along with prolonged half-life and enhanced animal tolerability.  In conclusion, through PEGylation of the traditional dipeptide linker, we have demonstrated an optimized ADC conjugation technology that can be employed for conjugating ultrahydrophobic payloads, thus enhancing both the therapeutic index and pharmacokinetics profile.

Langmuir. 2014 Jul 1;30(25):7465-74. doi: 10.1021/la500403v. Epub 2014 Jun 17. Effect of polyethylene glycol, alkyl, and oligonucleotide spacers on the binding, secondary structure, and self-assembly of fractalkine binding FKN-S2 aptamer-amphiphiles Abstract Previously we identified an aptamer, named FKN-S2, which binds the cell surface protein fractalkine with high affinity and specificity. In this paper a hydrophobic dialkyl C16 tail was added to the aptamer to create an aptamer-amphiphile. We investigated how the tail and a spacer molecule of varying length and hydrophobicity, inserted between the tail and the aptamer headgroup, affect the binding, structure, and self-assembly properties of the aptamer-amphiphile. We synthesized aptamer-amphiphiles with no spacer (NoSPR), polyethylene glycol (PEG4, PEG8, PEG24), alkyl (C12 and C24), or oligonucleotide (T10 and T5: 10 and 5 thymine, and A10: 10 adenine) spacers. The addition of the tail reduced the binding affinity of the aptamer-amphiphile over 7.5-fold compared to the free aptamer. The hydrophobic alkyl spacers resulted in the greatest loss of affinity, and the hydrophilic PEG spacers improved amphiphile affinity but did not restore it to that of the free aptamer. Interestingly, oligonucleotide spacers produced the highest affinity amphiphiles. Nucleotide composition did not affect affinity, however, as the T10 and A10 spacers had equal affinity. The oligonucleotide spacer amphiphiles had the highest affinity because the oligonucleotide spacer increased the affinity of free aptamer; the FKN-S2 aptamer plus the oligonucleotide spacer had a higher affinity than the free FKN-S2 aptamer. Circular dichroism (CD) spectroscopy and thermal melting studies indicated the aptamer forms a stem-loop and intramolecular G-quadruplex, and the tail strongly stabilized the formation of the G-quadruplex in a buffer. Cryogenic transmission electron microscopy (cryo-TEM) imaging showed the aptamer-amphiphiles, independent of the spacer used, self-assembled into micelles and nanotapes, flat bilayer structures that were often twisted. Finally, liposomes functionalized with the FKN-S2 amphiphile were incubated with fractalkine expressing cells, and the amount of binding was dependent on the concentration of the amphiphile on the liposome surface.

Biosens Bioelectron. 2019 Sep 15:141:111477. doi: 10.1016/j.bios.2019.111477. Epub 2019 Jun 25. Novel thiolated-PEG linker molecule for biosensor development on gold surfaces Abstract The surface modifying linker molecules can directly influence the performance and longevity of biosensors. They must allow the attachment of biological recognition layer on the sensor surface, as well as the protection of the surface from fouling effects. Recent advances in this field identified several key factors that can increase the efficiency, stability and the anti-fouling effect of a layer formed by surface modifying linker molecules. Herein, this work presents a simple synthetic procedure, characterization, and application of a novel thiolated-PEG surface modifying molecule (DSPEG2) that could act as a multi-purpose linker for gold surfaces. The analyses of the molecular spatial distribution of DSPEG2 on gold surfaces were performed using time-of-flight secondary ion mass spectrometry (TOF-SIMS) imaging and X-ray photoelectric spectroscopy (XPS). The immobilization of DSPEG2 on gold surfaces was examined using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and surface plasmon resonance (SPR). Our preliminary results demonstrated that DSPEG2 is a promising novel linker molecule that can be applied in a wide range of biosensors based on gold surfaces. Keywords: Anti-fouling; Biosensor; Cyclic voltammetry; Electrochemical impedance spectroscopy; Non-specific adsorption; PEG; Surface plasmon resonance; Synthetic linker.