Bioconjugate Chemistry最新文献

{"title":"Super-Sensitive Chemiluminescent Probe for the Detection of Caspase-3 Activity","authors":"Rozan Tannous,&nbsp;Chi Zhang and Doron Shabat*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0015110.1021/acs.bioconjchem.5c00151","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00151https://doi.org/10.1021/acs.bioconjchem.5c00151","url":null,"abstract":"<p >Caspase-3 is a pivotal enzyme in the apoptosis pathway that is responsible for executing programmed cell death through the cleavage of key cellular proteins. Existing fluorescence-based probes for caspase-3 detection suffer from limitations such as background noise from tissue autofluorescence and light scattering, reducing their sensitivity and real-time imaging capabilities. To overcome these limitations, we developed a chemiluminescent probe, Ac-DEVD-CL, that enables the highly sensitive and selective detection of caspase-3 activity. Upon caspase-3-mediated cleavage, the probe undergoes a self-immolative reaction that triggers a chemiluminescent signal, allowing real-time monitoring of the enzymatic activity. Probe Ac-DEVD-CL demonstrated an exceptionally high turn-on response, with a 5000-fold increase in the chemiluminescent signal upon enzymatic activation. The probe exhibited notable specificity for caspase-3, with minimal cross-reactivity toward other biologically relevant proteases and tumor-associated enzymes. Additionally, inhibition studies using the caspase-3 inhibitor confirmed that the probe’s activation is exclusively mediated by caspase-3. A direct comparison with the commercially available fluorescent probe revealed that probe Ac-DEVD-CL offers significantly improved sensitivity, achieving a signal-to-noise ratio 380-fold higher and a limit of detection 100-fold lower. These results establish probe Ac-DEVD-CL as a highly effective tool for detecting caspase-3 activity with superior precision. Finally, we validated the probe’s utility in imaging apoptosis in live cells. In 4T1 breast cancer cells treated with cisplatin, Ac-DEVD-CL generated a strong chemiluminescent signal, with a three-order-of-magnitude enhancement compared to untreated cells. Overall, the probe Ac-DEVD-CL demonstrates a significant improvement in detection sensitivity, providing a powerful and versatile chemiluminescent probe for real-time imaging of caspase-3 activity. Its exceptional sensitivity and selectivity could make it a valuable tool for cancer research, drug discovery, and therapeutic monitoring.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 5","pages":"1113–1120 1113–1120"},"PeriodicalIF":4.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.bioconjchem.5c00151","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144098193","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":"Cell Labeling with Responsive MRI Contrast Agents is Enabled through Solid-Phase Synthesis.","authors":"Liam Connah, Danijela Bataveljić, Aleksandra M Bondžić, Lucía Cabrera Fernández De Henestrosa, Andrej Korenić, Bojan P Bondžić, Pavle Andjus, Goran Angelovski","doi":"10.1021/acs.bioconjchem.5c00005","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00005","url":null,"abstract":"<p><p>Bioresponsive or smart contrast agents (SCAs) for magnetic resonance imaging (MRI) can facilitate functional molecular imaging of numerous biological processes. These are MRI probes that alter the MRI signal along with the concentration changes of different biomarkers in their microenvironment, thus enabling the assessment of tissue physiology with high spatiotemporal resolution. One of the common shortcomings of SCA is their structural and functional insufficiency for accumulation in the targeted region, i.e., most frequently internalization into the cells to study the intracellular processes. Here, we report a strategy to prepare a multifunctional SCA that can be successfully incorporated into the cell membrane and internalized. We used the solid-phase synthesis methodology to obtain a trimeric SCA responsive to calcium ions, which bears a hydrophobic tetradecanoyl group to facilitate interaction with primary rat astrocytes. The developed MRI probe maintained high activity, exhibiting high calcium-triggered longitudinal and transverse relaxivity changes. Concurrently, it showed the ability to label the cell membranes and internalize into the astroglial cells while not causing cytotoxicity or affecting the electrophysiology of the cells.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951271","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":"Elucidating Critical Factors of Internalization and Drug Release of Antibody-Drug Conjugates (ADCs) Using Kinetic Parameters Evaluated by a Novel Tool Named TORCH","authors":"Stanley Sweeney-Lasch*,&nbsp;Marie Quillmann,&nbsp;Jens Hannewald,&nbsp;Stephan Dickgiesser,&nbsp;Nicolas Rasche,&nbsp;Min Shan,&nbsp;Carl Deutsch,&nbsp;Stefan Hecht,&nbsp;Jan Anderl,&nbsp;Harald Kolmar and Birgit Piater,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0057910.1021/acs.bioconjchem.4c00579","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00579https://doi.org/10.1021/acs.bioconjchem.4c00579","url":null,"abstract":"<p >During the past decade, antibody-drug conjugates (ADCs) have emerged as new drugs in cancer therapy with 15 ADCs already approved such as Kadcyla, Enhertu, and Adcetris. ADCs contain a cytotoxic drug that is linked to an antibody, allowing for specific delivery of the warhead to tumor cells. Typically, the antibody targets a tumor-specific antigen expressed on the cell surface. After the internalization of ADCs into cells, the linker is often cleaved by enzymes in the lysosomal compartment of the cell, releasing the warhead and thereby allowing for its interaction with, for example, the DNA or the tubulin cytoskeleton, which finally leads to cell death. Consequently, binding, internalization, and drug release are key attributes for the efficacy of ADCs. Here, we describe a novel molecule named TORCH (Turn On after Release by CatHepsins) that contains a fluorescence quencher system that is separated by a cathepsin B-cleavable linker. When conjugated to an antibody, the TORCH molecule allows one to gain valuable insights on the internalization and drug release of ADCs. While we cannot exclude the influence of other factors such as receptor recycling, we have found that the receptor density is directly related to the amount of payload released intracellularly, meaning that the internalization per receptor is very similar for all investigated antibodies and cell lines.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 5","pages":"945–959 945–959"},"PeriodicalIF":4.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097946","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":"Bioorthogonally Activatable Photosensitizer for NIR Fluorescence Imaging-Guided Highly Selective Elimination of Senescent Tumor Cells and Chemotherapy Enhancement","authors":"Yun Feng,&nbsp;Zifan Zhu,&nbsp;Shirui Zhao,&nbsp;Xingyu Jiang,&nbsp;Wen Zhang and Zhiai Xu*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0010910.1021/acs.bioconjchem.5c00109","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00109https://doi.org/10.1021/acs.bioconjchem.5c00109","url":null,"abstract":"<p >Chemotherapy is a primary modality in cancer treatment, but it may induce cellular senescence, which in turn triggers the release of senescence-associated secretory phenotypes (SASPs) that promote tumor growth and metastasis. To selectively identify senescent cells and mitigate their negative impact on cancer therapy, herein, we have developed a β-galactosidase (β-Gal)-activated and self-immobilizing photosensitizer CyGF-DBCO-T. This photosensitizer can be selectively activated and fluorescently label proteins in situ within senescent cells, enabling near-infrared (NIR) fluorescence imaging-guided photodynamic therapy (PDT) for the precise ablation of these cells. First, we developed an activatable NIR fluorescent probe CyGF-N₃ that can specifically in situ label senescent cells. Subsequently, DBCO-T with free radicals underwent a bioorthogonal click reaction with activated CyGF-N₃ in senescent cells to generate the photosensitizer CyO-DBCO-T. Under light irradiation, CyO-DBCO-T generated singlet oxygen (¹O₂) in situ, thereby enabling precise PDT with fluorescence guidance and photoactivation. Both CyGF-N₃ and DBCO-T were encapsulated in biotinylated liposomes (CyGF-N₃@LIP-B and DBCO-T@LIP-B), which enhanced their water solubility, tumor targeting, and in vivo circulation time. This promoted the accumulation of the probes in senescent tumor cells, thus enabling intense fluorescence imaging of tumor senescence regions in mice and enhancing the efficacy of PDT. This dual-module strategy, guided by fluorescence imaging for PDT, has achieved selective identification and precise ablation of senescent tumor cells in a chemotherapy-induced senescence model, effectively alleviating chemotherapy resistance and suppressing tumor growth.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 5","pages":"1066–1078 1066–1078"},"PeriodicalIF":4.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097999","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":"Transduction of Glycan–Lectin Binding via an Impedimetric Sensor for Glycoprotein Detection","authors":"Linhui Lv,&nbsp; and ,&nbsp;Ke Qu*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0053010.1021/acs.bioconjchem.4c00530","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00530https://doi.org/10.1021/acs.bioconjchem.4c00530","url":null,"abstract":"<p >Glycoproteins are produced by glycosylation modification of proteins, and a number of glycoproteins have served as important tumor biomarkers in clinical application. Alpha-fetoprotein (AFP) is one of the representative glycoproteins that has been employed as a useful predictive and prognostic biomarker for hepatocellular carcinoma. Human AFP has an <i>N</i>-glycan portion at the asparagine residue, which includes four <i>N</i>-acetyl-glucosamine and three mannoses. In this work, building upon lectin–glycan interactions, one type of facile and capable impedimetric biosensor was fabricated utilizing microwave-prepared NH₂-MIL-101(Fe) to decorate lectins as a recognition element. Two different lectins of wheat-germ agglutinin (WGA) and concanavalin A (Con A) were employed to target the <i>N</i>-acetyl-glucosamine and mannose of <i>N</i>-glycan in AFP, respectively. This work has not only accomplished the sensitive impedimetric biosensing of the AFP tumor marker (with the limit of detection down to 0.5 pg/mL and linear concentration spanning 5 orders of magnitude from 10^–2 to 10³ ng/mL) but also replied on two kinds of lectins to “read” the sugar chain, transducing the minor difference of this process to impedimetric signals for display. The impedimetric data shed some light on the local microenvironment of the lectin–glycan binding event, providing some electrochemical experimental support for the biantennary structure of <i>N</i>-glycan in AFP. The mannoses were “buried” in the interior core of the whole <i>N</i>-glycan, increasing steric hindrance for Con A to approach and thus rendering the WGA@MIL-101(Fe)-based biosensor more superior sensing responses.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 5","pages":"936–944 936–944"},"PeriodicalIF":4.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097883","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":"Easy Access to Bioorthogonal Click-to-Release Reagent Bishydroxy-trans-cyclooctene (C2TCO) and Harnessing of Its Rapid Labeling and Dissecting Feature in Multicycle Imaging","authors":"V. Arun,&nbsp;Minju Lee,&nbsp;Hongseo Choi,&nbsp;Sangwoo Lee,&nbsp;Junwon Choi,&nbsp;Tae Hyeon Yoo,&nbsp;Wook Kim* and Eunha Kim*,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0049510.1021/acs.bioconjchem.4c00495","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00495https://doi.org/10.1021/acs.bioconjchem.4c00495","url":null,"abstract":"<p >Bifunctional <i>trans</i>-cyclooctene (bTCO) with a carbamate or carbonate at the allylic position and tetrazine provide a promising bioorthogonal click chemistry pair for the click-to-release approach, successfully employed in various biotechnological applications. Herein, we demonstrate a simple and straightforward method to synthesize C₂TCO, a symmetrical bTCO derivative with two hydroxyl groups at the allylic positions. The efficiently synthesized C₂TCO at first was selectively functionalized with a fluorophore (C₂TCO-FL), and the conjugate was labeled onto monoclonal antibodies (Ab-C₂TCO-FL). The fluorophore of Ab-C₂TCO-FL was easily removed from the antibody through the mild treatment of tetrazine, enabling multicycle fluorescent bioimaging. Next, an antibody-drug conjugate targeting PD-L1 was prepared using the linker based on C₂TCO. The cytotoxic payload was efficiently released from the antibody upon tetrazine treatment, which induced cellular cytotoxicity.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 5","pages":"930–935 930–935"},"PeriodicalIF":4.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144098264","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":"Redesigning Ibuprofen for Improved Oral Delivery and Reduced Side Effects","authors":"Szilvia H. Toth,&nbsp;Anca D. Stoica* and Cristian Sevcencu,&nbsp;","doi":"10.1021/acs.bioconjchem.4c0055810.1021/acs.bioconjchem.4c00558","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00558https://doi.org/10.1021/acs.bioconjchem.4c00558","url":null,"abstract":"<p >Ibuprofen (IBP) is one of the most widely used nonsteroidal anti-inflammatory drugs (NSAIDs). Being well-known for its efficacy, long history of use, and reduced adverse events compared to other NSAIDs, IBP is authorized as an analgesic and antipyretic drug. IBP’s mechanism of action consists of inhibiting cyclooxygenases, which are crucial oxidoreductases in prostaglandin synthesis and generation of inflammation and pain. However, despite being effective and relatively safe, IBP can still induce a dose-dependent toxicity which manifests mainly in the gastrointestinal system as ulcerations and altered mucosal blood flow and cytotoxicity characterized by mitochondrial dysfunction and increased membrane permeability in enterocytes and hepatocytes. Therefore, ongoing research is performed to improve the IBP’s activity and treatment outcome, and one way to achieve such improvements is through reducing IBP’s toxicity by designing less harmful but still effective novel IBP conjugates. The aim of this review is to summarize the latest achievements with IBP conjugation techniques that created such valuable IBP formulations less toxic than but as effective as the parent drug.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 5","pages":"893–913 893–913"},"PeriodicalIF":4.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144098157","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":"Development of a Long-Acting Myeloid-Derived Growth Factor via Site-Specific PEGylation","authors":"Yong-Shan Zheng,&nbsp;Teng Zhang,&nbsp;Ji-Yang Song,&nbsp;Mingchan Liang,&nbsp;Ya-Li Liu,&nbsp;Zeng-Guang Xu,&nbsp;Cheng He* and Zhan-Yun Guo*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0002610.1021/acs.bioconjchem.5c00026","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00026https://doi.org/10.1021/acs.bioconjchem.5c00026","url":null,"abstract":"<p >Extracellular myeloid-derived growth factor (MYDGF) can improve organ repair. However, short <i>in vivo</i> half-life hampers its therapeutic application. Herein, we developed a long-acting MYDGF via site-specific PEGylation at its C-terminus. Bacterially overexpressed human MYDGF carrying a C-terminal Asn-Ala-Leu tripeptide motif was first ligated with a synthetic azido-functionalized Gly-Ile-Gly-Lys(N3) tetrapeptide linker via catalysis of [G238 V]BmAEP1, an engineered bamboo-derived asparaginyl endopeptidase (AEP)-type peptide ligase. Thereafter, the azido-functionalized MYDGF was efficiently conjugated with a commercially available dibenzocyclooctyne (DBCO)-functionalized linear PEG30000 via copper-free click chemistry. The site-specifically PEGylated MYDGF (PEG-MYDGF) retained high <i>in vitro</i> activity and showed a much longer <i>in vivo</i> half-life in mice compared with unmodified MYDGF. In diabetic mice, PEG-MYDGF significantly promoted wound healing after subcutaneous injection. Thus, PEG-MYDGF represents a long-acting biologic with therapeutic potential. The present enzymatic peptide ligation and copper-free click chemistry-based approach could be applied to other proteins for site-specific conjugation with various functional moieties.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 5","pages":"993–1003 993–1003"},"PeriodicalIF":4.0,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144098155","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":"Comparative Study of Click Handle Stability in Common Ligation Conditions","authors":"Caitlin Fawcett,&nbsp;Joe Watson,&nbsp;Stephen Richards,&nbsp;Alfred E. Doherty,&nbsp;Hikaru Seki,&nbsp;Elizabeth A. Love,&nbsp;Charlotte H. Coles,&nbsp;Diane M. Coe and Craig Jamieson*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0009510.1021/acs.bioconjchem.5c00095","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00095https://doi.org/10.1021/acs.bioconjchem.5c00095","url":null,"abstract":"<p >Click chemistry efficiently ligates molecular building blocks in a robust and high-yielding manner and has found major application in the rapid modification of important molecular actors in biological systems. However, the high reactivity of click handles often correlates with decreased stability, which presents a significant challenge in the practical application of these systems. In the current study, we describe a survey of the stability of commonly deployed click manifolds across a range of widely used ligation conditions. Incompatible click handle and ligation condition combinations are identified, with kinetic half-lives and side products of each undesired reaction determined, including the assessment of stability over extended periods and in a protein environment. This data set provides researchers with a roadmap to expediently determine the most appropriate click reaction conditions for any given bioorthogonal application, thus elevating the probability of success of procedures that utilize click chemistry.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 5","pages":"1054–1065 1054–1065"},"PeriodicalIF":4.0,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.bioconjchem.5c00095","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144098154","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":"Mannosamine-Modified Poly(lactic-co-glycolic acid)-Polyethylene Glycol Nanoparticles for the Targeted Delivery of Rifapentine and Isoniazid in Tuberculosis Therapy","authors":"Cong Peng,&nbsp;Haopeng Luan,&nbsp;Qisong Shang,&nbsp;Wei Xiang,&nbsp;Parhat Yasin and Xinghua Song*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c0006210.1021/acs.bioconjchem.5c00062","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.5c00062https://doi.org/10.1021/acs.bioconjchem.5c00062","url":null,"abstract":"<p >Tuberculosis, caused by <i>Mycobacterium tuberculosis</i>, is the leading cause of mortality attributed to a single infectious agent. Following macrophage invasion, M. tuberculosis uses various mechanisms to evade immune responses and to resist antituberculosis drugs. This study aimed to develop a targeted drug delivery system utilizing mannosamine (MAN)-modified nanoparticles (NPs) composed of poly(lactic-<i>co</i>-glycolic acid)–polyethylene glycol (PLGA–PEG), loaded with rifapentine and isoniazid, to enhance macrophage-directed therapy and enhance bacterial elimination. PLGA–PEG copolymer was modified with mannosamine through an amidation reaction. Rifapentine- and isoniazid-loaded PLGA–PEG-MAN NPs were synthesized by using the double emulsion solvent evaporation technique. The NPs exhibited an average particle size of 117.67 nm and displayed favorable physicochemical properties without evidence of cellular or hemolytic toxicity. The drug loading rates were 11.73% for rifapentine and 5.85% for isoniazid. Sustained drug release was achieved over a period exceeding 72 h, with antibacterial activity remaining intact during encapsulation. Synergistic bactericidal effects were noted. Additionally, mannosamine-modified NPs enhanced the phagocytic activity of macrophages via mannose receptor-mediated endocytosis, thereby improving drug delivery efficiency and significantly boosting the antibacterial efficacy of the NPs within macrophages. Pathological staining and biochemical analysis of rat organs following intravenous injection indicated that the NPs did not cause any significant toxic side effects in vivo. The findings of this study indicate that mannosamine-modified PLGA–PEG NPs loaded with rifapentine and isoniazid represent a promising drug delivery system for targeting macrophages to enhance the efficacy of antitubercular therapy.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 5","pages":"1021–1033 1021–1033"},"PeriodicalIF":4.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.bioconjchem.5c00062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144098096","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}