Bioconjugate Chemistry最新文献

{"title":"ImmunoPET Demonstrates that Co-Targeting GD2 and B7–H3 with Bispecific Antibodies Enhances Tumor Selectivity in Preclinical Melanoma Models","authors":"Zachary T. Rosenkrans,&nbsp;Amy K. Erbe,&nbsp;Nathan B. Clemons,&nbsp;Arika S. Feils,&nbsp;Yadira Medina-Guevara,&nbsp;Justin J. Jeffery,&nbsp;Todd E. Barnhart,&nbsp;Jonathan W. Engle,&nbsp;Paul M. Sondel and Reinier Hernandez*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00016","DOIUrl":"10.1021/acs.bioconjchem.5c00016","url":null,"abstract":"<p >Disialoganglioside 2 (GD2) is overexpressed in multiple cancers, such as melanoma and neuroblastoma, but also in peripheral nerves. To improve current GD2-targeting approaches, next-generation heterodimeric bispecific human IgG antibodies were created, each with one antibody binding fragment (Fab) arm specific for GD2 and the other Fab arm specific for B7–H3 (CD276) to drive tumor selectivity. The avidity and selectivity of our GD2–B7-H3 targeting bispecific antibodies (INV34–6, INV33–2, and INV36–6) were determined by flow cytometry and competition binding assays in GD2⁺/hB7-H3⁺ B78 cells. INV34–6 showed high avidity for GD2⁺/hB7-H3⁺ but not GD2⁺/hB7-H3^– B78 cells, contrasting with the similar cell binding to these cells observed with the anti-GD2 antibody Dinutuximab (DINU). The bispecific antibodies, DINU, and a nontargeted bispecific control (bsAb CTRL) were conjugated with deferoxamine for radiolabeling with Zr-89 (<i>t</i>_1/2 = 78.4 h). Positron emission tomography (PET) corroborated the in vivo avidity and selectivity of the GD2–B7-H3 targeting bispecific compared to bsAb CTRL and DINU in GD2⁺/hB7-H3⁺ and GD2⁺/hB7-H3^– B78 tumor models. PET in mice bearing the GD2⁺/hB7-H3^– and GD2⁺/hB7-H3⁺ B78 murine xenografts showed similar biodistribution in normal tissues for [⁸⁹Zr]Zr-Df-INV34–6, [⁸⁹Zr]Zr-Df-bsAb CTRL, and [⁸⁹Zr]Zr-Df-DINU. Importantly, [⁸⁹Zr]Zr-Df-INV34–6 tumor uptake was selective to GD2⁺/hB7-H3⁺ B78 over GD2⁺/hB7-H3^– B78 tumors, unlike [⁸⁹Zr]Zr-Df-DINU, which displayed elevated tumor uptake, irrespective of hB7-H3 expression. Nontargeted [⁸⁹Zr]Zr-Df-bsAb CTRL isotype control showed markedly lower uptake in all tested tumor models. Overall, bispecific antibodies binding GD2 and B7–H3 showed improved selectivity for targeting tumor cells expressing both antigens. This approach may enhance antitumor efficacy while addressing the toxicity limitations of current GD2-targeting therapies by reducing off-tumor GD2 binding in nerves.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1595–1603"},"PeriodicalIF":3.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144751828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Topological Switch-OFF and β-Galactosidase-Triggered Switch-ON of Cyclic Antisense Oligonucleotides via CuAAC for Controlled RNA Cleavage","authors":"Kento Miyaji*,&nbsp;Keita Takeuchi and Kohji Seio,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00295","DOIUrl":"10.1021/acs.bioconjchem.5c00295","url":null,"abstract":"<p >Prodrug-type antisense oligonucleotides (ASOs) offer spatiotemporal control of gene silencing via external stimuli or intracellular enzyme activation. However, a robust dual switch-off mechanism for phosphorothioate (PS)-modified gapmer ASOs, particularly involving topological constraints, has been largely unexplored. This study aimed to design and synthesize novel β-galactosidase-responsive cyclic ASOs that achieve controlled RNA cleavage through both inhibited Watson–Crick base pairing and topological constraints. Cyclic structures were efficiently constructed via optimized copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC), tailored for PS-modified ASOs to ensure high cyclization yields and minimal desulfurization. UV-melting analyses and RNase H-mediated RNA cleavage assays confirmed a pronounced dual switch-off effect in the cyclic ASOs bearing triple cross-linking or double cross-linking with a modification positioned at the center of the loop. Upon β-galactosidase treatment, galactose-conjugated linkers were efficiently removed, restoring duplex stability and RNase H-mediated RNA cleavage to levels comparable to those of native ASOs, demonstrating switch-on functionality. This activation was observed under both neutral and acidic conditions. This strategy establishes a practical chemical foundation for developing next-generation oligonucleotide therapeutics, enabling precise spatiotemporal control of gene silencing.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1820–1837"},"PeriodicalIF":3.9,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00295","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144751829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"iLOV3.0 Fluorescent Probes for Monitoring ROS Changes in Mammalian Cells","authors":"Shuhui Zhang,&nbsp;Chongyuan Ye,&nbsp;Linyun Guo,&nbsp;Xiaokun Jian,&nbsp;Long Hua,&nbsp;Tangyuan Xie,&nbsp;Tian Huang* and Gengsheng Cao*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00208","DOIUrl":"10.1021/acs.bioconjchem.5c00208","url":null,"abstract":"<p >Monitoring global ROS levels in mammalian cells is essential for capturing redox dynamics that influence both normal physiology and disease progression. Here, we mutated the fluorescent protein iLOV to become more sensitive to ROS in mammalian cells. This mutation enabled the long-term dynamic monitoring of ROS changes in mammalian cells. We confirmed that the mutated iLOV3.0 protein is more sensitive to redox reactions than the iLOV1.0 protein. The iLOV3.0 probe is broadly applicable to mammalian cells, capable of targeting organelles, and exhibits time- and dose-dependent responses to oxidants and reductants while also monitoring ROS changes caused by cellular nutrient stress and alterations in redox-related enzymes. Importantly, the iLOV3.0 probe can track ROS fluctuations during iPSC induction and viral invasion. In summary, this study developed a reactive oxygen species monitoring tool based on the iLOV protein that can be used for mammalian cell imaging. This probe directly utilizes the photophysical properties of iLOV to respond to ROS and undergo fluorescence signal changes without requiring exogenous cofactors. This method is expected to make up for the limitations of existing ROS monitoring tools and provide a new technical means for the dynamic study of the redox states in living cells.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1709–1720"},"PeriodicalIF":3.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of Coiled-Coil Affinity Peptides to Manufacture Antibody Conjugates","authors":"Seyed Farzad Baniahmad,&nbsp;Alina Burlacu,&nbsp;Laurence Delafosse,&nbsp;Mauro Acchione,&nbsp;Miriam Simmons,&nbsp;Binbing Ling,&nbsp;Umar Iqbal,&nbsp;Maria J Moreno,&nbsp;Gregory De Crescenzo and Yves Durocher*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00178","DOIUrl":"10.1021/acs.bioconjchem.5c00178","url":null,"abstract":"<p >Antibody-drug conjugates are revolutionizing cancer treatment. However, their manufacturing still requires improvements in conjugation technology, especially for the control of the drug-to-antibody ratio (DAR). Here, we investigate the use of the de novo designed coiled-coil heterodimer, composed of the Ecoil and Kcoil peptides, as a new strategy for generating antibody conjugates with high homogeneity and a controllable DAR. More precisely, we investigated the assembly, stability, and tumor targeting of two conjugated antibodies made of (1) trastuzumab with C-terminal Ecoils (TZM-Ecoil) noncovalently paired with Kcoil peptides fused to the monomeric red fluorescent protein (Kcoil-mRFP), yielding TZM-E/K-mRFP or (2) TZM-Ecoil noncovalently paired to Kcoil peptide covalently linked to the fluorescent dye CF750 (Kcoil-CF750), yielding TZM-E/K-CF750. Results from the <i>in vitro</i> stability assessment of these complexes in blood serum revealed that their integrity was maintained. Furthermore, <i>in vivo</i> biodistribution and tumor localization data using a HER2-expressing SKOV3 xenograft mouse model indicated efficient tumor targeting and retention for up to 10 days postinjection of the TZM-E/K-CF750 conjugate.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1670–1682"},"PeriodicalIF":3.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00178","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Membrane Repair Proteins as Negative Regulators of Cytosolic Delivery Using Attenuated Cationic Lytic Peptide L17E and Cell-Penetrating Peptides: Differences and Similarities","authors":"Masashi Kuriyama,&nbsp;Yoshimasa Kawaguchi,&nbsp;Shinji Ito,&nbsp;Junko Satoh,&nbsp;Hisaaki Hirose* and Shiroh Futaki*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00177","DOIUrl":"10.1021/acs.bioconjchem.5c00177","url":null,"abstract":"<p >Cytosolic delivery of functional macromolecules is beneficial for intracellular targeting. Although numerous intracellular delivery methods have been developed, the biological factors that govern their efficacy remain poorly understood, thereby limiting further advancement of existing approaches. L17E is an attenuated cationic amphiphilic lytic (ACAL) peptide developed by our research group that facilitates the cytosolic delivery of macromolecules, including antibodies and functional proteins. The L17E peptide exhibits varying levels of cytosolic delivery even within a single cell line, suggesting heterogeneity in the cellular sensitivity to the delivery process. Based on the hypothesis that the specific proteins contribute to this variability, HeLa cells were sorted into L17E-sensitive and L17E-insensitive populations. Comparative proteome analysis of the membrane fractions of these two groups revealed that annexin A2, a membrane repair-related protein, was more abundant in L17E-insensitive cells. Time-lapse imaging and knockdown experiments indicated that annexin A2 negatively regulates L17E-mediated cytosolic delivery by sealing the plasma membrane regions permeabilized by the L17E peptide. To assess whether membrane repair factors also influence cytosolic delivery via conventional cell-penetrating peptides (CPPs), we examined the roles of repair-related proteins. We found that the endosomal sorting complex required for transport (ESCRT) suppressed the cytosolic translocation of the CPPs, whereas annexin A2 did not. These findings suggest that the L17E peptide and the CPPs utilize distinct membrane repair-associated pathways during delivery and that the expression levels of these repair factors affect delivery efficiency. Modulating such factors may therefore provide a strategy for enhancing peptide-based cytosolic delivery systems.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1683–1697"},"PeriodicalIF":3.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanoenabled Strategies Enhancing PROTACs for Cancer Therapy","authors":"Rui Li,&nbsp;Shuhao Zhang,&nbsp;Yunxue Xu,&nbsp;Renfa Liu and Zhifei Dai*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00305","DOIUrl":"10.1021/acs.bioconjchem.5c00305","url":null,"abstract":"<p >Proteolysis-targeting chimeras (PROTACs) have emerged as a breakthrough therapeutic strategy in oncology, enabling the selective degradation of traditionally “undruggable” proteins via the ubiquitin-proteasome system. However, their clinical translation remains challenging due to high molecular weight, limited aqueous solubility, and metabolic instability, which limit systemic bioavailability and tumor penetration. To address these challenges, a variety of nanocarrier systems have been developed to improve the stability, pharmacokinetics, and tumor-specific accumulation of PROTACs. Beyond delivery enhancement, nanotechnology also enables the creation of next-generation PROTAC modalities, such as mRNA-encoded and RNA-scaffolded PROTACs, thereby expanding their therapeutic potential. In parallel, stimuli-responsive nanocarriers offer spatiotemporal control over PROTAC release, maximizing therapeutic efficacy while minimizing off-target effects. This review provides a comprehensive overview of nanotechnology-enabled strategies for PROTAC delivery, highlights key translational challenges, and discusses future directions to facilitate their clinical advancement in cancer therapy.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1582–1587"},"PeriodicalIF":3.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Vacuo Glycation of Poly(l-Lysine): A Simple Method to Install Pendent Sugars","authors":"Jaehak Yu,&nbsp;Xiaoli Liang and Elizabeth R. Gillies*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00279","DOIUrl":"10.1021/acs.bioconjchem.5c00279","url":null,"abstract":"<p >Glycopolymers are valuable for biomedical applications due to their ability to mimic natural glycoconjugates, yet current synthetic methods often require complex chemistries or do not produce native linkages. Here, we report a simple in vacuo glycation method to functionalize poly(<span>l</span>-lysine) (PLL) with pendent sugars, inspired by natural nonenzymatic glycation. PLL was incubated with various reducing sugars in vacuo at elevated temperatures, enabling efficient conjugation via native-like ketoamine linkages without additional chemical modifications or activating agents. The best evaluated conditions for <span>d</span>-glucose involved 4 sugar equivalents, pH 8, and 65 °C, yielding &gt;95% functionalization with minimal advanced glycation end-product (AGE) formation or cross-linking. Aldohexoses such as <span>d</span>-mannose and <span>d</span>-galactose were also successfully conjugated under slightly modified conditions (70 and 60 °C, respectively), while ketoses, pentoses, and trioses led to insoluble, cross-linked products due to increased AGE formation. Reducing disaccharides exhibited limited conversion, likely due to steric hindrance. Structural characterization confirmed efficient sugar installation and preservation of polymer solubility. This in vacuo glycation approach offers a straightforward, biomimetic route to glycopolymer synthesis from amine-bearing polymers, expanding the toolkit for designing bioinspired materials for biomedical and material science applications.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1797–1806"},"PeriodicalIF":3.9,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innovative Glucagon-like Peptide 1 Receptor Agonists: Exploring the Therapeutic Potential of Specific Modified Monomer, Dimer, and Tetramer in Type 2 Diabetes Treatment","authors":"Yan Du,&nbsp;Tao Liu,&nbsp;Hua-Lin Li,&nbsp;Qun Luo,&nbsp;Xiao-Yuan Guo,&nbsp;Jian-Yun Wang,&nbsp;Xin-Rui Wang,&nbsp;Ya-Man Zhou,&nbsp;Ya-Wen Pan,&nbsp;Li-Cheng Yu,&nbsp;Hong-Mei Tan,&nbsp;Ke-Sheng Hu and Song-Shan Tang*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00261","DOIUrl":"10.1021/acs.bioconjchem.5c00261","url":null,"abstract":"<p >Modified glucagon-like peptide 1 (GLP-1) plays a crucial role in type 2 diabetes (T2D) treatment. The comparative hypoglycemic effect among fatty-acid-modified GLP-1 monomer G20, dimer 2G21, and tetramer 4G18 was evaluated in T2D mice. The polymers exhibited an opposite solubility with their monomers. After single administration, the oral glucose tolerance test results showed that the monomers, dimer, or tetramer, respectively, had 3–9, 21, or 35 days of hypoglycemic effect or plasma stability. G20 had a moderate hypoglycemic effect, and its peak effect occurred in week 1 as semaglutide. 2G21 showed a strongly hypoglycemic effect in week 1–10, and its peak effect occurred in week 4. 4G18 had a weak effect initially but rapidly strengthened in weeks 6–10 and reached its peak effect in week 10. After the 10 week interference, compared to the model control group, G20 (−19.7 or −4.3%), 2G21-L/M/H (−15.9/–34.3/–26.7% or −6.0/–34.4/–36.2%), and 4G18-L/M/H groups (−44.3/–49.8/–53.8% or −40.9/–50.6/–50.8%) significantly exhibited hypoglycemic effects in postprandial glucose or fasting plasma glucose changes. Insulin altered +4.1% (G20), −9.6/+10.0/+36.5% (2G21-L/M/H), and +38.5/+28.7/+84.8% (4G18-L/M/H). HbA_1c or body weight reduced −11.9 or −0.18% (G20), −5.2/–15.2/–19.1% or +0.5/–4.7/–1.2% (2G21-L/M/H), and −5.8/–4.8/–5.4% or −2.9/–2.1/–3.1% (4G18-L/M/H), showing a dose-dependent reduction in 2G21, whereas the 4G18 had lower variations. 2G21 induced a hypoglycemic effect and diet stress, whereas 4G18 only did a hypoglycemic effect and showed a stronger protection to the model organs and more improvement in the nerve muscle than G20 or 2G21. The endogenous insulin release depends not only on the GLP-1 peptide dose but also on the peptide chain in the polymer skeleton.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1753–1766"},"PeriodicalIF":3.9,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Metal-Free Click Reactions: New Frontiers in Glycochemistry and Bioconjugation","authors":"Pedro Ramírez-López,&nbsp;José Ramón Suárez,&nbsp;Aida Flores and María J. Hernáiz*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00049","DOIUrl":"10.1021/acs.bioconjchem.5c00049","url":null,"abstract":"<p >Efficient and biocompatible methods for synthesizing glycoconjugates are essential in chemical biology, as these molecules play pivotal roles in cellular recognition, signaling, and immune responses. Abnormal glycosylation is associated with diseases such as cancer, infections, and immune disorders, positioning glycoconjugates as promising candidates for therapeutic, diagnostic, and drug delivery applications. Traditional chemical approaches often lack biocompatibility and efficiency; however, the advent of metal-free click chemistry has revolutionized glycoconjugate synthesis by providing selective and versatile tools under mild conditions. This review highlights four remarkable metal-free click reactions: thiol–ene coupling (TEC), strain-promoted azide–alkyne cycloaddition (SPAAC), inverse electron-demand Diels–Alder (IEDDA) reaction, and sulfur fluoride exchange (SuFEx). TEC enables the regio- and stereoselective synthesis of glycoconjugates, including S-polysaccharides, glycopeptides, and glycoclusters, advancing vaccine development and carbohydrate-based therapeutics. SPAAC, a bioorthogonal and metal-free alternative, facilitates <i>in vivo</i> imaging, glycan monitoring, the synthesis of glycofullerenes and glycovaccines, and the development of targeted protein degradation systems such as lysosome-targeting chimeras (LYTACs). Additionally, the combination of SPAAC with biocatalysis offers a sustainable approach for preparing glycoconjugates with therapeutic potential. The IEDDA reaction, a highly efficient metal-free biorthogonal cycloaddition, plays a key role in metabolic glycoengineering for live-cell imaging and glycan-based therapies and also contributes to the creation of injectable hydrogels for drug delivery and tissue engineering. SuFEx, a more recent reaction, enables efficient sulfonamide and sulfonate bond formation, broadening the toolbox for glycoconjugate and protein functionalization. These methodologies are transforming glycochemistry and glycobiology, driving advancements in biomedicine, materials science, and pharmaceutical development.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1553–1581"},"PeriodicalIF":3.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144647968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enzymatic Cellular Nanoparticles Deliver Payloads across Mucosal Barriers","authors":"Luke J. Kubiatowicz,&nbsp;Nima N. Pourafzal,&nbsp;Nishta Krishnan,&nbsp;Lin Bao,&nbsp;Animesh Mohapatra,&nbsp;Weiwei Gao,&nbsp;Ronnie H. Fang* and Liangfang Zhang*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00262","DOIUrl":"10.1021/acs.bioconjchem.5c00262","url":null,"abstract":"<p >Patient preferred routes of administration for therapeutics and prophylactics, such as via oral delivery and inhalation, require penetration through mucosal barriers to achieve effective bioavailability. The mucus layer is composed of glycosylated mucin proteins and serves as a robust natural defense against pathogens but also significantly impedes the delivery of medicinal agents. To overcome this barrier, we developed an innovative virus-mimicking enzymatic cellular nanoparticle designed to enhance mucopenetration. Inspired by the influenza A virus, we genetically engineered the neuraminidase protein onto the surface of mammalian cell membrane, which was subsequently used to coat mRNA-loaded lipid nanoparticle cores. This enabled the resulting nanoparticles to cleave sialic acid residues within the mucus matrix, thereby facilitating mucopenetration. In vitro studies demonstrated that these enzyme-coated cellular nanoparticles effectively traversed an artificial mucus layer, significantly enhancing mRNA delivery to underlying epithelial cells. Furthermore, in vivo experiments in a murine model showed improved lung expression of the mRNA payload after intratracheal administration. By harnessing the power of viral biomimicry, this work unveils exciting possibilities for overcoming mucosal barriers.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 8","pages":"1767–1774"},"PeriodicalIF":3.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}