Pub Date : 2026-02-01DOI: 10.1016/j.biopha.2026.119047
Paola Chiodelli , Andrea Papait , Lorenzo Agoni , Federico Quaglia , Antonietta Rosa Silini , Ornella Parolini
Despite the tumor microenvironment (TME) being a major therapeutic focus, the clinical translation of TME-targeted agents has been largely unsuccessful, a paradox that challenges paradigms rooted in a reductionist view of the TME as a self-contained entity. We propose a framework redefining the TME as an open, multi-scalar ecosystem dynamically shaped by systemic host factors. Locally, cancer-associated fibroblasts (CAFs), myeloid cells and the vasculature act not as isolated cell types but as integrated components of functional niches that orchestrate fibrosis, immunosuppression and angiogenesis. Systemically, the gut microbiome and chronic inflammation of ageing (‘inflammaging’) pre-condition the host terrain and modulate therapeutic responses across this network. Viewed through this systemic lens, resistance emerges not as molecular bypass but as ecological adaptation of a complex, open system. We argue that next-generation therapies will depend on spatial omics to map pathological niches and on rational, multimodal strategies that explicitly target the TME as a systemically integrated network.
{"title":"The tumor ecosystem: Rewiring an open, systemically integrated network for therapeutic gain","authors":"Paola Chiodelli , Andrea Papait , Lorenzo Agoni , Federico Quaglia , Antonietta Rosa Silini , Ornella Parolini","doi":"10.1016/j.biopha.2026.119047","DOIUrl":"10.1016/j.biopha.2026.119047","url":null,"abstract":"<div><div>Despite the tumor microenvironment (TME) being a major therapeutic focus, the clinical translation of TME-targeted agents has been largely unsuccessful, a paradox that challenges paradigms rooted in a reductionist view of the TME as a self-contained entity. We propose a framework redefining the TME as an open, multi-scalar ecosystem dynamically shaped by systemic host factors. Locally, cancer-associated fibroblasts (CAFs), myeloid cells and the vasculature act not as isolated cell types but as integrated components of functional niches that orchestrate fibrosis, immunosuppression and angiogenesis. Systemically, the gut microbiome and chronic inflammation of ageing (‘inflammaging’) pre-condition the host terrain and modulate therapeutic responses across this network. Viewed through this systemic lens, resistance emerges not as molecular bypass but as ecological adaptation of a complex, open system. We argue that next-generation therapies will depend on spatial omics to map pathological niches and on rational, multimodal strategies that explicitly target the TME as a systemically integrated network.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119047"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.biopha.2026.119071
Xiping Liang, Xiaomei Zhang, Chaoyu Wang, Chunyan Xiao, Xiaoqing Xie, Yixing Zhou, Wenwen Zhou, Yao Liu
Introduction
Despite improved outcomes in diffuse large B-cell lymphoma (DLBCL) with rituximab-based therapy, cell adhesion-mediated drug resistance (CAM-DR) remains a key mechanism of treatment resistance. The role of follistatin-like protein 1 (FSTL1) in CAM-DR has not been fully elucidated.
Methods
We conducted a retrospective analysis of newly diagnosed DLBCL patients treated with rituximab from 2019 to 2024, with special emphasis on FSTL1 expression and clinical features, and its underlying mechanism.
Results
FSTL1 was detectable in 74.5 % of patients. Its expression was significantly elevated in DLBCL patients compared to controls (P < 0.05) and was further increased in the RR-DLBCL group (P = 0.045). FSTL1 patients exhibited more adverse clinical features, including higher incidence of extranodal involvement, more advanced stage, elevated LDH levels, and bulky masses (all p < 0.05). FSTL1 expression patients revealed a shorter overall survival (OS) (p = 0.024) and progression-free survival (PFS) (p = 0.034), with similar trend in high FSTL1 expression (P < 0.05). In vitro, increased exogenous of FSTL1 contributed to DLBCL cell proliferation, vitality, and decreased the antibody-dependent cellular cytotoxicity (ADCC) effect, whereas FSTL1 silencing reversed this trend (P < 0.05). Pathway enrichment analysis revealed an association between FSTL1 and CAM-DR. Mechanistic experiments revealed that FSTL1 may be derived from secretion by cancer-associated fibroblasts (CAFs), interacts with DIP2A on DLBCL cells and promotes ICAM-1 expression, thereby contributing to drug resistance in DLBCL.
Conclusion
Our findings indicate that elevated FSTL1 levels may contribute to advanced clinical characteristics and worse outcomes in DLBCL. FSTL1 contributes to drug resistance likely through DIP2a/ICAM-1-mediated adhesion mechanism.
{"title":"FSTL1 contribute to aggressive clinical behavior in DLBCL may by activating the DIP2A/ICAM-1-mediated adhesion mechanism","authors":"Xiping Liang, Xiaomei Zhang, Chaoyu Wang, Chunyan Xiao, Xiaoqing Xie, Yixing Zhou, Wenwen Zhou, Yao Liu","doi":"10.1016/j.biopha.2026.119071","DOIUrl":"10.1016/j.biopha.2026.119071","url":null,"abstract":"<div><h3>Introduction</h3><div>Despite improved outcomes in diffuse large B-cell lymphoma (DLBCL) with rituximab-based therapy, cell adhesion-mediated drug resistance (CAM-DR) remains a key mechanism of treatment resistance. The role of follistatin-like protein 1 (FSTL1) in CAM-DR has not been fully elucidated.</div></div><div><h3>Methods</h3><div>We conducted a retrospective analysis of newly diagnosed DLBCL patients treated with rituximab from 2019 to 2024, with special emphasis on FSTL1 expression and clinical features, and its underlying mechanism.</div></div><div><h3>Results</h3><div>FSTL1 was detectable in 74.5 % of patients. Its expression was significantly elevated in DLBCL patients compared to controls (P < 0.05) and was further increased in the RR-DLBCL group (P = 0.045). FSTL1 patients exhibited more adverse clinical features, including higher incidence of extranodal involvement, more advanced stage, elevated LDH levels, and bulky masses (all p < 0.05). FSTL1 expression patients revealed a shorter overall survival (OS) (p = 0.024) and progression-free survival (PFS) (p = 0.034), with similar trend in high FSTL1 expression (P < 0.05). In vitro, increased <strong>exogenous of</strong> FSTL1 contributed to DLBCL cell proliferation, vitality, and decreased the antibody-dependent cellular cytotoxicity (ADCC) effect, whereas FSTL1 silencing reversed this trend (P < 0.05). Pathway enrichment analysis revealed an association between FSTL1 and CAM-DR. Mechanistic experiments revealed that FSTL1 may be derived from secretion by cancer-associated fibroblasts (CAFs), interacts with DIP2A on DLBCL cells and promotes ICAM-1 expression, thereby contributing to drug resistance in DLBCL.</div></div><div><h3>Conclusion</h3><div>Our findings indicate that elevated FSTL1 levels may contribute to advanced clinical characteristics and worse outcomes in DLBCL. FSTL1 contributes to drug resistance likely through DIP2a/ICAM-1-mediated adhesion mechanism.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119071"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.biopha.2026.119039
Yannan Xiang , Tianyue Guan , Jun Wang , Shasha Zhang , Yusa Li , Jing Xia , Panpan Zhao , Lei Wang
This study explores the protective effects of Atraric Acid (AA) against chronic kidney disease (CKD) induced by a high-fat diet (HFD) and its underlying mechanisms. In vivo HFD-induced CKD mouse models and in vitro OA/PA-stimulated HK2 cells were treated with AA. AA improved kidney morphology, reduced fibrosis, lipid accumulation, and body weight. It also decreased serum TC, TG, HDL-C, Scr, BUN, and Cys-C levels, indicating improved renal function. AA alleviated oxidative stress, ROS accumulation, and inflammation, as confirmed by DHE staining, oxidative stress markers, and pro-inflammatory cytokine levels. Western blotting showed that AA activated Nrf2 and suppressed NF-κB signaling. AMPK inhibition experiments demonstrated that AA regulated Nrf2 and NF-κB via AMPKα phosphorylation. In conclusion, AA mitigates HFD-induced CKD by targeting AMPKα to regulate oxidative stress and inflammation.
{"title":"Atraric acid alleviates high-fat diet-induced renal injury, lipid accumulation, and fibrosis in mice by regulating oxidative stress and inflammation through AMPK-dependent Nrf2 and NF-κB signaling pathways","authors":"Yannan Xiang , Tianyue Guan , Jun Wang , Shasha Zhang , Yusa Li , Jing Xia , Panpan Zhao , Lei Wang","doi":"10.1016/j.biopha.2026.119039","DOIUrl":"10.1016/j.biopha.2026.119039","url":null,"abstract":"<div><div>This study explores the protective effects of Atraric Acid (AA) against chronic kidney disease (CKD) induced by a high-fat diet (HFD) and its underlying mechanisms. In vivo HFD-induced CKD mouse models and in vitro OA/PA-stimulated HK2 cells were treated with AA. AA improved kidney morphology, reduced fibrosis, lipid accumulation, and body weight. It also decreased serum TC, TG, HDL-C, Scr, BUN, and Cys-C levels, indicating improved renal function. AA alleviated oxidative stress, ROS accumulation, and inflammation, as confirmed by DHE staining, oxidative stress markers, and pro-inflammatory cytokine levels. Western blotting showed that AA activated Nrf2 and suppressed NF-κB signaling. AMPK inhibition experiments demonstrated that AA regulated Nrf2 and NF-κB via AMPKα phosphorylation. In conclusion, AA mitigates HFD-induced CKD by targeting AMPKα to regulate oxidative stress and inflammation.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119039"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.biopha.2026.119063
Jun Wang , Ouyang Su , Zhaoxu Meng , Lili Lu , Yake Qi , Zonghui Zhang , Zhou Li , Xiu Dong , He Lian , Yiping Mu
Oxidative stress plays a crucial role in the development of various diseases, including diabetes, cardiovascular diseases, cancer, and rheumatic disorders. It disrupts the redox balance and initiates a series of pathological changes. As two-dimensional inorganic solids with an open structure and anion-exchange properties, layered double hydroxides (LDHs) offer significant advantages in the biomedical field, such as drug carriers, antioxidant catalysts. This article outlines application of LDHs in the treatment of cancer, rheumatic diseases, bone disorders, diabetes, Alzheimer's disease, and other conditions. More importantly, this paper elaborates on the challenges faced by the application of LDHs, including the biological activity to be explored, the performance to be optimized, and their in vivo functions and molecular mechanisms to be clarified. The solution strategies have also been discussed, which pointed out the direction for promoting the clinical transformation and application of LDHs in the future.
{"title":"Layered double hydroxide-induced modulation of oxidative stress in disease therapy","authors":"Jun Wang , Ouyang Su , Zhaoxu Meng , Lili Lu , Yake Qi , Zonghui Zhang , Zhou Li , Xiu Dong , He Lian , Yiping Mu","doi":"10.1016/j.biopha.2026.119063","DOIUrl":"10.1016/j.biopha.2026.119063","url":null,"abstract":"<div><div>Oxidative stress plays a crucial role in the development of various diseases, including diabetes, cardiovascular diseases, cancer, and rheumatic disorders. It disrupts the redox balance and initiates a series of pathological changes. As two-dimensional inorganic solids with an open structure and anion-exchange properties, layered double hydroxides (LDHs) offer significant advantages in the biomedical field, such as drug carriers, antioxidant catalysts. This article outlines application of LDHs in the treatment of cancer, rheumatic diseases, bone disorders, diabetes, Alzheimer's disease, and other conditions. More importantly, this paper elaborates on the challenges faced by the application of LDHs, including the biological activity to be explored, the performance to be optimized, and their <em>in vivo</em> functions and molecular mechanisms to be clarified. The solution strategies have also been discussed, which pointed out the direction for promoting the clinical transformation and application of LDHs in the future.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119063"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.biopha.2026.119055
Na Li , Yu Zhao , Xianyun Jiang , Deyu Ran , Yihao Wang , Lin Zheng , Zhengkai Wang
Acute myocardial infarction (MI) causes tremendous damage to the coronary microcirculation, resulting in vascular disintegration and capillary rarefaction in the infarct area. Tissue repair after myocardial infarction (MI) is multifaceted. The mechanism of angiogenesis is complex and difficult to target, and the blood vessels that need to be revascularized extend from the infarct border zone to the necrotic infarct core1. Mirdametinib (PD0325901), a MEK inhibitor, promotes angiogenesis and has beneficial effects on ischemic hearts. However, its side effects have limited its application, and Mirdametinib has not yet met clinical requirements for how to treat diseases more safely, effectively and economically. Here, we present a multifunctional biomimetic nanoparticle drug delivery system consisting of Macrophage Membranes and Liposomes nanoparticles (MM&Lipo nanoparticles) for the targeted delivery of Mirdametinib (PD0325901) to induce ischemic tissue revascularization after acute MI. Compared with artificial liposomes, the MM&Lipo nanoparticle delivery system has the advantages of immune escape and strong activation of endothelial cell targeting. Additionally, MM&Lipo nanoparticles release sufficient PD0325901 in a controlled manner. In an induced MI model, it significantly improved cardiac function and infarct extent in mice. Compared with the PBS group after MI, the ejection fraction of MM&Lipo group recovered from 35 ± 3–82 ± 3, and the fractional shortening from 17 ± 2–50 ± 1. The area of fibrosis was also reduced from 25 ± 4 % to 11 ± 5. The key inflammatory factor marker TNF-α also decreased from 570 ± 31 pg/mL to 475 ± 70 pg/mL.Our findings demonstrate the important potential value of multifunctional biomimetic drug delivery systems that integrate macrophage membranes and liposomes as novel membrane materials in the treatment of post-MI revascularization.
{"title":"Liposomes and macrophage membrane co-assembled biomimetic nanoparticles alleviate cardiac insufficiency after myocardial infarction","authors":"Na Li , Yu Zhao , Xianyun Jiang , Deyu Ran , Yihao Wang , Lin Zheng , Zhengkai Wang","doi":"10.1016/j.biopha.2026.119055","DOIUrl":"10.1016/j.biopha.2026.119055","url":null,"abstract":"<div><div>Acute myocardial infarction (MI) causes tremendous damage to the coronary microcirculation, resulting in vascular disintegration and capillary rarefaction in the infarct area. Tissue repair after myocardial infarction (MI) is multifaceted. The mechanism of angiogenesis is complex and difficult to target, and the blood vessels that need to be revascularized extend from the infarct border zone to the necrotic infarct core<sup>1</sup>. Mirdametinib (PD0325901), a MEK inhibitor, promotes angiogenesis and has beneficial effects on ischemic hearts. However, its side effects have limited its application, and Mirdametinib has not yet met clinical requirements for how to treat diseases more safely, effectively and economically. Here, we present a multifunctional biomimetic nanoparticle drug delivery system consisting of Macrophage Membranes and Liposomes nanoparticles (MM&Lipo nanoparticles) for the targeted delivery of Mirdametinib (PD0325901) to induce ischemic tissue revascularization after acute MI. Compared with artificial liposomes, the MM&Lipo nanoparticle delivery system has the advantages of immune escape and strong activation of endothelial cell targeting. Additionally, MM&Lipo nanoparticles release sufficient PD0325901 in a controlled manner. In an induced MI model, it significantly improved cardiac function and infarct extent in mice. Compared with the PBS group after MI, the ejection fraction of MM&Lipo group recovered from 35 ± 3–82 ± 3, and the fractional shortening from 17 ± 2–50 ± 1. The area of fibrosis was also reduced from 25 ± 4 % to 11 ± 5. The key inflammatory factor marker TNF-α also decreased from 570 ± 31 pg/mL to 475 ± 70 pg/mL.Our findings demonstrate the important potential value of multifunctional biomimetic drug delivery systems that integrate macrophage membranes and liposomes as novel membrane materials in the treatment of post-MI revascularization.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119055"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.biopha.2026.119070
Peter U. Amadi , Justice O. Osuoha , Joy.A. Amadi , Esienanwan E. Efiong , Prince C. Odika , Celestine E. Ekweogu , Chioma Ejiofor , Govind S. Gill , Suha J. Jarad , Chiamaka W. Amadi , Hongmei Gu , Barbora de Courten , Emmanuel N. Agomuo , Dawei Zhang
Background
Metabolic-dysfunction associated steatohepatitis (MASH) arises from sustained triglyceride overload of the intestine-liver axis, yet current therapies rarely coordinate intestinal lipid entry with hepatic triglyceride disposal. Here we identify a phenolic-acid fraction as a dual-compartment metabolic modulator that couples intestinal lipase inhibition to CPT1α-PPARα-dependent hepatic β-oxidation across species.
Methods
Across species, we investigated the kinetics and metabolic actions of a phenolic fraction (PhAM) using recombinant lipase systems, epithelial transport assays, hepatocyte models, pharmacokinetics, diet-induced metabolic disease paradigms, quantitative histopathology, and a 24-week randomized placebo-controlled clinical trial.
Results
PhAM selectively suppresses pancreatic and intestinal lipases non-competitively, lowering V_max with minimal K_m change, resembling some features of orlistat, but via a distinct, non-covalent mechanism. In Caco-2 monolayers and ex vivo loops, it reduces apical-to-basolateral fatty-acid flux, depletes intracellular triglycerides, and limits luminal-to-plasma lipid transfer. PhAM is orally bioavailable, with measurable plasma exposure and prolonged intestinal residence. Under high-fat feeding, it increases fecal fat loss, attenuates post-lipid-load triglyceride excursions, and lowers hepatic triglycerides without altering ApoB secretion. Its triglyceride-lowering effect requires CPT1α-dependent mitochondrial import and PPARα activation, elevates β-hydroxybutyrate, and induces oxidative genes while sparing lipogenesis. In chronic MASH, PhAM reduces steatosis, ballooning, inflammation, and metabolic-dysfunction associated steatotic liver disease (MASLD) Activity Score. A 24-week clinical subgroup, defined by ultrasound and transaminase enrichment, showed dose-responsive improvements in ultrasonographic steatosis and metabolic biomarkers.
Conclusion
Collectively, these findings define PhAM as a phenolic-acid-based agent that aligns intestinal lipid restriction with hepatic oxidative unloading, offering a mechanistically coherent framework for potentially addressing steatotic liver disease-associated metabolic features.
{"title":"Dual intestinal-hepatic modulation by phenolic acids improves metabolic-dysfunction associated steatohepatitis","authors":"Peter U. Amadi , Justice O. Osuoha , Joy.A. Amadi , Esienanwan E. Efiong , Prince C. Odika , Celestine E. Ekweogu , Chioma Ejiofor , Govind S. Gill , Suha J. Jarad , Chiamaka W. Amadi , Hongmei Gu , Barbora de Courten , Emmanuel N. Agomuo , Dawei Zhang","doi":"10.1016/j.biopha.2026.119070","DOIUrl":"10.1016/j.biopha.2026.119070","url":null,"abstract":"<div><h3>Background</h3><div>Metabolic-dysfunction associated steatohepatitis (MASH) arises from sustained triglyceride overload of the intestine-liver axis, yet current therapies rarely coordinate intestinal lipid entry with hepatic triglyceride disposal. Here we identify a phenolic-acid fraction as a dual-compartment metabolic modulator that couples intestinal lipase inhibition to CPT1α-PPARα-dependent hepatic β-oxidation across species.</div></div><div><h3>Methods</h3><div>Across species, we investigated the kinetics and metabolic actions of a phenolic fraction (PhAM) using recombinant lipase systems, epithelial transport assays, hepatocyte models, pharmacokinetics, diet-induced metabolic disease paradigms, quantitative histopathology, and a 24-week randomized placebo-controlled clinical trial.</div></div><div><h3>Results</h3><div>PhAM selectively suppresses pancreatic and intestinal lipases non-competitively, lowering V_max with minimal K_m change, resembling some features of orlistat, but via a distinct, non-covalent mechanism. In Caco-2 monolayers and ex vivo loops, it reduces apical-to-basolateral fatty-acid flux, depletes intracellular triglycerides, and limits luminal-to-plasma lipid transfer. PhAM is orally bioavailable, with measurable plasma exposure and prolonged intestinal residence. Under high-fat feeding, it increases fecal fat loss, attenuates post-lipid-load triglyceride excursions, and lowers hepatic triglycerides without altering ApoB secretion. Its triglyceride-lowering effect requires CPT1α-dependent mitochondrial import and PPARα activation, elevates β-hydroxybutyrate, and induces oxidative genes while sparing lipogenesis. In chronic MASH, PhAM reduces steatosis, ballooning, inflammation, and metabolic-dysfunction associated steatotic liver disease (MASLD) Activity Score. A 24-week clinical subgroup, defined by ultrasound and transaminase enrichment, showed dose-responsive improvements in ultrasonographic steatosis and metabolic biomarkers.</div></div><div><h3>Conclusion</h3><div>Collectively, these findings define PhAM as a phenolic-acid-based agent that aligns intestinal lipid restriction with hepatic oxidative unloading, offering a mechanistically coherent framework for potentially addressing steatotic liver disease-associated metabolic features.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119070"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.biopha.2026.119016
Zijie Chen , Xiaotong Song , Yongxiang Zheng, Shuwen Zhang, Rong Yu, Chun Zhang
Bispecific antibodydrug conjugates represent an innovative concept for cancer therapy, which integrates the merits of both antibodydrug conjugates and bispecific antibodies. In this study, a proof-of-concept biomimetic bispecific antibody based on an albumin binding domain fusing with camelid-derived nanobodies was devised to deliver anti-cancer drugs to replicate the two most distinctive features of ADCs: long-acting in vivo and tumor targeting, while reducing products heterogeneity and production cost. To validate this concept, an anti-EGFR nanobody and an anti-HER2 nanobody were used as model sequences to construct biomimetic bispecific antibodies. The biomimetic bispecific antibodies were efficiently expressed in Escherichia coli bacteria and produced at considerably low cost, and the model cytotoxic payload (mc-vc-PAB-MMAE) were site-specifically coupled to the fusion protein through a cysteine-maleimide based conjugation approach. These bispecific protein-MMAE conjugates were well characterized in vitro, and exhibited prolonged circulation times in healthy rats and superior anti-tumor efficacy in an A549 xenograft mice model. The works could provide a general strategy for design of biomimetic bispecific ADCs for cancer therapies.
{"title":"Biomimetic bispecific antibody-drug conjugates based on albumin binding domain fusing nanobodies targeting EGFR and HER2","authors":"Zijie Chen , Xiaotong Song , Yongxiang Zheng, Shuwen Zhang, Rong Yu, Chun Zhang","doi":"10.1016/j.biopha.2026.119016","DOIUrl":"10.1016/j.biopha.2026.119016","url":null,"abstract":"<div><div>Bispecific antibody<img>drug conjugates represent an innovative concept for cancer therapy, which integrates the merits of both antibody<img>drug conjugates and bispecific antibodies. In this study, a proof-of-concept biomimetic bispecific antibody based on an albumin binding domain fusing with camelid-derived nanobodies was devised to deliver anti-cancer drugs to replicate the two most distinctive features of ADCs: long-acting <em>in vivo</em> and tumor targeting, while reducing products heterogeneity and production cost. To validate this concept, an anti-EGFR nanobody and an anti-HER2 nanobody were used as model sequences to construct biomimetic bispecific antibodies. The biomimetic bispecific antibodies were efficiently expressed in <em>Escherichia coli</em> bacteria and produced at considerably low cost, and the model cytotoxic payload (mc-vc-PAB-MMAE) were site-specifically coupled to the fusion protein through a cysteine-maleimide based conjugation approach. These bispecific protein-MMAE conjugates were well characterized <em>in vitro</em>, and exhibited prolonged circulation times in healthy rats and superior anti-tumor efficacy in an A549 xenograft mice model. The works could provide a general strategy for design of biomimetic bispecific ADCs for cancer therapies.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119016"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号