Pub Date : 2025-12-01DOI: 10.1016/j.apsb.2025.10.029
Honglei Wang , Zibei Wu , Chen Gao , Wenhao Wang , Minglong Chen , Lin Yuan , Jiating Wang , Cairong Xiao , Yang Zhou , Fan Tong , Hanmei Li , Huile Gao , Xiang Gao , Jintao Fu
Probiotic therapy offers a promising strategy for chronic infected wound management through pathogen suppression and immune modulation. However, its efficacy remains restricted by weak competitiveness in pathogen-rich niches and poor penetration across biofilm barriers. Inspired by bacterial competitive interactions, we developed a multifunctional microneedle (MN) platform to overcome these limitations. Lactobacillus reuteri (Lr) was coated with poly-l-lysine-modified metal–phenolic networks (MPNs) encapsulating doxorubicin (DOX), yielding DOX@MPN–PLL@Lr (DMP@Lr). The engineered probiotics were incorporated into dissolving MNs enriched with nutrient broth to ensure excellent microneedle performance and probiotic function. This design leverages MPN multifunctionality to reduce early-stage pathogenic burden via photothermal-assisted bacterial killing and near-infrared (NIR)-promoted antibiotic release, thereby enhancing probiotic competitiveness. Meanwhile, MNs physically disrupt biofilms for precise delivery into deep infection sites. In vitro, DMP@Lr achieved >99.9% (5.5 log) bactericidal efficiency, and its MNs exhibited a 1.4-fold higher biofilm clearance compared with blank MNs. In vivo, a single DMP@Lr MN patch promoted 93.9% wound closure, demonstrating potent antibacterial activity and accelerated healing. This study presents an innovative, translatable probiotic-based MN therapy for the effective treatment of chronically infected wounds.
{"title":"Probiotic living microneedles designed by interbacterial competition for accelerated infected wound healing","authors":"Honglei Wang , Zibei Wu , Chen Gao , Wenhao Wang , Minglong Chen , Lin Yuan , Jiating Wang , Cairong Xiao , Yang Zhou , Fan Tong , Hanmei Li , Huile Gao , Xiang Gao , Jintao Fu","doi":"10.1016/j.apsb.2025.10.029","DOIUrl":"10.1016/j.apsb.2025.10.029","url":null,"abstract":"<div><div>Probiotic therapy offers a promising strategy for chronic infected wound management through pathogen suppression and immune modulation. However, its efficacy remains restricted by weak competitiveness in pathogen-rich niches and poor penetration across biofilm barriers. Inspired by bacterial competitive interactions, we developed a multifunctional microneedle (MN) platform to overcome these limitations. <em>Lactobacillus reuteri</em> (Lr) was coated with poly-<span>l</span>-lysine-modified metal–phenolic networks (MPNs) encapsulating doxorubicin (DOX), yielding DOX@MPN–PLL@Lr (DMP@Lr). The engineered probiotics were incorporated into dissolving MNs enriched with nutrient broth to ensure excellent microneedle performance and probiotic function. This design leverages MPN multifunctionality to reduce early-stage pathogenic burden <em>via</em> photothermal-assisted bacterial killing and near-infrared (NIR)-promoted antibiotic release, thereby enhancing probiotic competitiveness. Meanwhile, MNs physically disrupt biofilms for precise delivery into deep infection sites. <em>In vitro</em>, DMP@Lr achieved >99.9% (5.5 log) bactericidal efficiency, and its MNs exhibited a 1.4-fold higher biofilm clearance compared with blank MNs. <em>In vivo</em>, a single DMP@Lr MN patch promoted 93.9% wound closure, demonstrating potent antibacterial activity and accelerated healing. This study presents an innovative, translatable probiotic-based MN therapy for the effective treatment of chronically infected wounds.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6571-6586"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.apsb.2025.09.030
Guoqing Wang , Kai Wu , Zongliang Zhang , Yongdong Chen , Yanfang Li , Xiaoshuang Jiang , Licong Liang , Yiliu Yang , Hongsong Fan , Jing Sun , Aiping Tong , Fang Lu
Retinoblastoma (RB) is the most common primary ocular malignancy in children, arising from the developing retina. While higher doses of local chemotherapy have improved tumor control, concerns regarding retinal toxicity and the development of chemoresistance remain significant. Oncolytic adenovirus (OA) presents a promising therapeutic approach for RB, but rapid clearance often limits its therapeutic effects. In this study, we engineered a genetically modified OA derived from human adenovirus 5 (Ad5), designed to selectively target and lyse RB cells. The combination of OA with low-dose melphalan demonstrates an enhanced antitumor effect, while minimizing retinal toxicity. In vitro and in vivo experiments demonstrated that melphalan significantly enhanced the antitumor effect of OA and extended ocular survival. More importantly, we developed a biocompatible injectable hydrogel delivery system based on the covalent coupling of collagen and aldehyde-modified cyclodextrin, which effectively enhances the loading efficiency of melphalan and enables sustained co-delivery of OA and melphalan. The mouse RB tumor model confirmed that this hydrogel system (OA-Mel@CCA) achieved localized and sustained delivery of both therapeutics, effectively controlling tumor growth and preventing brain metastasis. Additionally, retinal structure and function were notably preserved in mice treated with OA-Mel@CCA, with no observed retinal toxicity. These findings suggest that the injectable hydrogel-based co-delivery of melphalan and oncolytic adenovirus could represent a promising strategy for RB treatment.
{"title":"Injectable hydrogel-mediated co-delivery of oncolytic adenovirus and melphalan for retinoblastoma control and vision preservation","authors":"Guoqing Wang , Kai Wu , Zongliang Zhang , Yongdong Chen , Yanfang Li , Xiaoshuang Jiang , Licong Liang , Yiliu Yang , Hongsong Fan , Jing Sun , Aiping Tong , Fang Lu","doi":"10.1016/j.apsb.2025.09.030","DOIUrl":"10.1016/j.apsb.2025.09.030","url":null,"abstract":"<div><div>Retinoblastoma (RB) is the most common primary ocular malignancy in children, arising from the developing retina. While higher doses of local chemotherapy have improved tumor control, concerns regarding retinal toxicity and the development of chemoresistance remain significant. Oncolytic adenovirus (OA) presents a promising therapeutic approach for RB, but rapid clearance often limits its therapeutic effects. In this study, we engineered a genetically modified OA derived from human adenovirus 5 (Ad5), designed to selectively target and lyse RB cells. The combination of OA with low-dose melphalan demonstrates an enhanced antitumor effect, while minimizing retinal toxicity. <em>In vitro</em> and <em>in vivo</em> experiments demonstrated that melphalan significantly enhanced the antitumor effect of OA and extended ocular survival. More importantly, we developed a biocompatible injectable hydrogel delivery system based on the covalent coupling of collagen and aldehyde-modified cyclodextrin, which effectively enhances the loading efficiency of melphalan and enables sustained co-delivery of OA and melphalan. The mouse RB tumor model confirmed that this hydrogel system (OA-Mel@CCA) achieved localized and sustained delivery of both therapeutics, effectively controlling tumor growth and preventing brain metastasis. Additionally, retinal structure and function were notably preserved in mice treated with OA-Mel@CCA, with no observed retinal toxicity. These findings suggest that the injectable hydrogel-based co-delivery of melphalan and oncolytic adenovirus could represent a promising strategy for RB treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6638-6656"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.apsb.2025.09.043
Lu Gan , Xincheng Lin , Ziqiao Zhong , Yichun Zheng , Xinyi Chen , Jun Chen , Xiao Yue , Yingshan Liu , Xin Pan , Chuanbin Wu , Ying Huang , Wenhao Wang
The integration of ferroptosis induction with cancer immunotherapy has emerged as a promising approach in oncology, offering dual mechanisms to overcome therapeutic resistance and tumor heterogeneity. Nevertheless, the dynamic and complicated crosstalk between ferroptosis processes and immune regulation in tumor microenvironments presents both opportunities and challenges. By inducing lipid peroxidation in tumor tissues, ferroptotic tumor cell death can stimulate immunogenicity. Nevertheless, excessive lipid peroxidation may paradoxically impair the functionality of multiple immune cells, thereby presenting crosstalk challenges in therapeutic strategies. To address these crosstalk challenges, several advanced drug delivery strategies have been proposed, such as immunostimulatory active pharmaceutical ingredients co-delivery, tumor-targeted delivery, and stimuli-responsive delivery. These drug delivery strategies demonstrate dual therapeutic efficacy by synergistically potentiating ferroptosis induction in malignant cells while concurrently mitigating immunotoxicity and even augmenting antitumor immunity. This review offers detailed insights into the crosstalk between ferroptosis and tumor immunity, along with a guiding overview of the three delivery strategies. The current obstacles and translational potential were thoroughly analyzed, providing valuable perspectives for future research.
{"title":"Ferroptosis meets cancer immunotherapy: Overcoming the crosstalk challenges through advanced drug delivery strategies","authors":"Lu Gan , Xincheng Lin , Ziqiao Zhong , Yichun Zheng , Xinyi Chen , Jun Chen , Xiao Yue , Yingshan Liu , Xin Pan , Chuanbin Wu , Ying Huang , Wenhao Wang","doi":"10.1016/j.apsb.2025.09.043","DOIUrl":"10.1016/j.apsb.2025.09.043","url":null,"abstract":"<div><div>The integration of ferroptosis induction with cancer immunotherapy has emerged as a promising approach in oncology, offering dual mechanisms to overcome therapeutic resistance and tumor heterogeneity. Nevertheless, the dynamic and complicated crosstalk between ferroptosis processes and immune regulation in tumor microenvironments presents both opportunities and challenges. By inducing lipid peroxidation in tumor tissues, ferroptotic tumor cell death can stimulate immunogenicity. Nevertheless, excessive lipid peroxidation may paradoxically impair the functionality of multiple immune cells, thereby presenting crosstalk challenges in therapeutic strategies. To address these crosstalk challenges, several advanced drug delivery strategies have been proposed, such as immunostimulatory active pharmaceutical ingredients co-delivery, tumor-targeted delivery, and stimuli-responsive delivery. These drug delivery strategies demonstrate dual therapeutic efficacy by synergistically potentiating ferroptosis induction in malignant cells while concurrently mitigating immunotoxicity and even augmenting antitumor immunity. This review offers detailed insights into the crosstalk between ferroptosis and tumor immunity, along with a guiding overview of the three delivery strategies. The current obstacles and translational potential were thoroughly analyzed, providing valuable perspectives for future research.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6307-6341"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.apsb.2025.09.039
Jinping Tao , Ling Liang , Siqi Hao , Yan Chen , Zhi Yang , Yimao Cai , Hua Zhu
Artificial intelligence (AI)-driven data-centric paradigms are catalyzing a paradigm shift in radiopharmaceutical development and molecular imaging, two pivotal technologies that underpin precision nuclear medicine. This review focuses on the cutting-edge applications of AI in radiopharmaceutical discovery and molecular image analytics, and systematically investigates the technical principles and typical cases of Deep Learning algorithms (e.g., Graph Neural Networks (GNNs), Generative Adversarial Networks (GANs), and Transformer Models) in target identification, ligand design, pharmacokinetic optimization, and image reconstruction and enhancement. By integrating multi-omics data and 3D structural information, AI can significantly improve the accuracy of target affinity prediction for radiopharmaceuticals and accelerate the design of novel ligands. In the field of molecular imaging, AI-driven low-dose single-photon emission computed tomography (SPECT) and positron emission tomography (PET) image reconstruction, tumor segmentation, and quantitative analysis techniques have significantly improved the diagnostic efficiency and accuracy, providing a reliable basis for individualized treatment. In addition, the paper discusses data privacy, model generalization, and ethical challenges faced by AI in clinical translation, and looks forward to the future direction of multidisciplinary integration (e.g., combining AI with radiochemistry and nuclear medicine) and technological innovations, which will help precision medicine leap from theory to practice.
{"title":"Artificial intelligence for radiopharmaceutical and molecular imaging","authors":"Jinping Tao , Ling Liang , Siqi Hao , Yan Chen , Zhi Yang , Yimao Cai , Hua Zhu","doi":"10.1016/j.apsb.2025.09.039","DOIUrl":"10.1016/j.apsb.2025.09.039","url":null,"abstract":"<div><div>Artificial intelligence (AI)-driven data-centric paradigms are catalyzing a paradigm shift in radiopharmaceutical development and molecular imaging, two pivotal technologies that underpin precision nuclear medicine. This review focuses on the cutting-edge applications of AI in radiopharmaceutical discovery and molecular image analytics, and systematically investigates the technical principles and typical cases of Deep Learning algorithms (<em>e.g.</em>, Graph Neural Networks (GNNs), Generative Adversarial Networks (GANs), and Transformer Models) in target identification, ligand design, pharmacokinetic optimization, and image reconstruction and enhancement. By integrating multi-omics data and 3D structural information, AI can significantly improve the accuracy of target affinity prediction for radiopharmaceuticals and accelerate the design of novel ligands. In the field of molecular imaging, AI-driven low-dose single-photon emission computed tomography (SPECT) and positron emission tomography (PET) image reconstruction, tumor segmentation, and quantitative analysis techniques have significantly improved the diagnostic efficiency and accuracy, providing a reliable basis for individualized treatment. In addition, the paper discusses data privacy, model generalization, and ethical challenges faced by AI in clinical translation, and looks forward to the future direction of multidisciplinary integration (<em>e.g</em>., combining AI with radiochemistry and nuclear medicine) and technological innovations, which will help precision medicine leap from theory to practice.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6199-6221"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.apsb.2025.10.004
Xinyue Wang , Xuetao Chen , Shuai Wen , Yi Mou , Xiaoke Guo , Zhengyu Jiang
N6-methyladenosine (m6A) represents the most abundant and functionally significant RNA modification implicated in epigenetic regulation, significantly impacting gene expression through the selective recognition by m6A reader proteins. Aberrant expression of m6A readers has been associated with cancer progression, contributing to tumor growth, metastasis, drug resistance, and immune evasion. With the increasing research on m6A readers, the discovery of small-molecule inhibitors targeting these proteins has emerged as a promising avenue for cancer therapy. This review delineates the classification and functional roles of m6A readers across various cancers. Furthermore, we summarize and discuss the recent progress in the development of small-molecule inhibitors, with a focus on the medicinal chemistry perspectives. We hope to provide valuable insights to guide future efforts in drug discovery and rational design targeting m6A readers for innovative cancer therapeutics.
{"title":"m6A readers: Promising therapeutic targets in cancer treatment","authors":"Xinyue Wang , Xuetao Chen , Shuai Wen , Yi Mou , Xiaoke Guo , Zhengyu Jiang","doi":"10.1016/j.apsb.2025.10.004","DOIUrl":"10.1016/j.apsb.2025.10.004","url":null,"abstract":"<div><div><em>N</em><sup>6</sup>-methyladenosine (m<sup>6</sup>A) represents the most abundant and functionally significant RNA modification implicated in epigenetic regulation, significantly impacting gene expression through the selective recognition by m<sup>6</sup>A reader proteins. Aberrant expression of m<sup>6</sup>A readers has been associated with cancer progression, contributing to tumor growth, metastasis, drug resistance, and immune evasion. With the increasing research on m<sup>6</sup>A readers, the discovery of small-molecule inhibitors targeting these proteins has emerged as a promising avenue for cancer therapy. This review delineates the classification and functional roles of m<sup>6</sup>A readers across various cancers. Furthermore, we summarize and discuss the recent progress in the development of small-molecule inhibitors, with a focus on the medicinal chemistry perspectives. We hope to provide valuable insights to guide future efforts in drug discovery and rational design targeting m<sup>6</sup>A readers for innovative cancer therapeutics.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6178-6198"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.apsb.2025.09.035
Jing Feng , Yingying Hu , Xiuxiu Sun , Yutong Hao , Yiyang Li , Qiang Huang , Yanli Xie , Jin Gao , Ange Hu , Yang Hong , Xu Wang , Heng Liu , Zijia Dou , Lina Yao , Qi Lu , Jennifer Wang , Philipp Kopylov , Weina Han , Yong Zhang , Xin Liu
Atherosclerosis is a chronic vascular disease closely associated with endothelial dysfunction. Ferroptosis, a major factor in endothelial dysfunction, plays a pivotal role in the progression of atherosclerosis. The development of drugs targeting endothelial ferroptosis offers a potential therapeutic approach for atherosclerosis. This study aimed to assess the potential impact of tetrahydroberberrubine (THBru) on atherosclerosis and unravel its molecular mechanism underlying endothelial protection. Our results demonstrated that THBru significantly reduced plaque formation in the aortas of atherosclerotic mice. Through transcriptome sequencing and further verification, we observed that THBru mitigated endothelial ferroptosis in atherosclerosis by enhancing glutathione homeostasis and decreasing reactive oxygen species (ROS) accumulation. Mechanistically, bioinformatic analysis demonstrated that THBru reduced the expression of the super-enhancer (SE) regulatory gene ATP-binding cassette subfamily C member 1 (ABCC1). The transcription factor BTB and CNC homology 1 (BACH1) was responsible for ABCC1 transcription by binding to its SE (ABCC1-SE), whereas THBru effectively inhibited the activity of ABCC1-SE. Furthermore, THBru promoted adenosine monophosphate-activated protein kinase (AMPK) activation, thereby negatively regulating BACH1 and the downstream ABCC1/ferroptosis signaling pathway. Collectively, these findings highlight THBru as a promising candidate for treating atherosclerosis, featuring a novel mechanism that inhibits endothelial ferroptosis through the AMPK/BACH1 axis to regulate ABCC1-SE.
{"title":"THBru ameliorates atherosclerosis by inhibiting endothelial ferroptosis via regulation of the super-enhancer-associated ABCC1","authors":"Jing Feng , Yingying Hu , Xiuxiu Sun , Yutong Hao , Yiyang Li , Qiang Huang , Yanli Xie , Jin Gao , Ange Hu , Yang Hong , Xu Wang , Heng Liu , Zijia Dou , Lina Yao , Qi Lu , Jennifer Wang , Philipp Kopylov , Weina Han , Yong Zhang , Xin Liu","doi":"10.1016/j.apsb.2025.09.035","DOIUrl":"10.1016/j.apsb.2025.09.035","url":null,"abstract":"<div><div>Atherosclerosis is a chronic vascular disease closely associated with endothelial dysfunction. Ferroptosis, a major factor in endothelial dysfunction, plays a pivotal role in the progression of atherosclerosis. The development of drugs targeting endothelial ferroptosis offers a potential therapeutic approach for atherosclerosis. This study aimed to assess the potential impact of tetrahydroberberrubine (THBru) on atherosclerosis and unravel its molecular mechanism underlying endothelial protection. Our results demonstrated that THBru significantly reduced plaque formation in the aortas of atherosclerotic mice. Through transcriptome sequencing and further verification, we observed that THBru mitigated endothelial ferroptosis in atherosclerosis by enhancing glutathione homeostasis and decreasing reactive oxygen species (ROS) accumulation. Mechanistically, bioinformatic analysis demonstrated that THBru reduced the expression of the super-enhancer (SE) regulatory gene ATP-binding cassette subfamily C member 1 (ABCC1). The transcription factor BTB and CNC homology 1 (BACH1) was responsible for <em>ABCC1</em> transcription by binding to its SE (<em>ABCC1</em>-SE), whereas THBru effectively inhibited the activity of <em>ABCC1</em>-SE. Furthermore, THBru promoted adenosine monophosphate-activated protein kinase (AMPK) activation, thereby negatively regulating BACH1 and the downstream ABCC1/ferroptosis signaling pathway. Collectively, these findings highlight THBru as a promising candidate for treating atherosclerosis, featuring a novel mechanism that inhibits endothelial ferroptosis through the AMPK/BACH1 axis to regulate <em>ABCC1</em>-SE.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6461-6477"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.apsb.2025.10.003
Xifeng Qin , Ruizhe Xu , Jiayi Wu , Yue Liu , Ting Wang , Hongyan Tu , Jia Li , Zhiqing Pang
Until now, although nanomedicines have gained much success in tumor treatment by reducing severe toxic side effects of drugs and improving the therapeutic efficiency of drugs, they are still faced with thorny challenges in targeted drug delivery including insufficient targeting accuracy, poor penetration into tumor core, and systemic toxicity issues. Recently, engineering nano/microrobots with multiple remarkable properties such as real-time sensing, interacting and manipulating capabilities, and programmability, have received increasing attention in biomedical applications ranging from disease diagnosis, targeted drug delivery, medical imaging, and surgery. More importantly, in different driven modes, nano/microrobots are capable of performing a wide variety of powerful functions, such as enhancing tissue penetration and payload retention in deep-seated tumors with active navigation, being programmable to release drugs or performing specific tasks directly at the tumor site with high precision and accuracy, automating repeated tumor treatment without the need for frequent interventions, and minimizing out-of-target tissue damage, leading to a huge exploration potential in tumor treatment. In this review, we delve into the recent progress and the development direction of nano/microrobots for tumor treatment and emphasize the working mechanisms and the unique functionalities of different driven modes in detail. Meanwhile, we elaborate on the application of nano/microrobots fabricated from various types of materials in tumor therapy. Finally, the key factors to be considered in the clinical translation of the above nano/microrobots are proposed.
{"title":"Recent advances in engineering nano/microrobots for tumor treatment","authors":"Xifeng Qin , Ruizhe Xu , Jiayi Wu , Yue Liu , Ting Wang , Hongyan Tu , Jia Li , Zhiqing Pang","doi":"10.1016/j.apsb.2025.10.003","DOIUrl":"10.1016/j.apsb.2025.10.003","url":null,"abstract":"<div><div>Until now, although nanomedicines have gained much success in tumor treatment by reducing severe toxic side effects of drugs and improving the therapeutic efficiency of drugs, they are still faced with thorny challenges in targeted drug delivery including insufficient targeting accuracy, poor penetration into tumor core, and systemic toxicity issues. Recently, engineering nano/microrobots with multiple remarkable properties such as real-time sensing, interacting and manipulating capabilities, and programmability, have received increasing attention in biomedical applications ranging from disease diagnosis, targeted drug delivery, medical imaging, and surgery. More importantly, in different driven modes, nano/microrobots are capable of performing a wide variety of powerful functions, such as enhancing tissue penetration and payload retention in deep-seated tumors with active navigation, being programmable to release drugs or performing specific tasks directly at the tumor site with high precision and accuracy, automating repeated tumor treatment without the need for frequent interventions, and minimizing out-of-target tissue damage, leading to a huge exploration potential in tumor treatment. In this review, we delve into the recent progress and the development direction of nano/microrobots for tumor treatment and emphasize the working mechanisms and the unique functionalities of different driven modes in detail. Meanwhile, we elaborate on the application of nano/microrobots fabricated from various types of materials in tumor therapy. Finally, the key factors to be considered in the clinical translation of the above nano/microrobots are proposed.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6222-6252"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The bromodomain-containing protein 9 (BRD9) is a core subunit of mammalian SWI/SNF chromatin remodeling complex termed ncBAF. BRD9 has emerged as a potential target for anticancer drugs, particularly in the treatment of acute myeloid leukemia (AML). Herein, we reported 10m (Y22073) and 10t as new BRD9 selective bromodomain inhibitors. Crystallographic studies revealed that the key active imidazolyl group discovered from structure-activity relationship (SAR) can induce Phe163 flipping and significantly enhance the cellular potency of the compounds, making 10m the first BRD9 selective inhibitor with significant cellular activity against AML cells. We also validated the critical role of imidazolyl groups by modifying existing BRD9 inhibitors. The representative compounds 10m and 10t demonstrated potent binding affinity, outstanding selectivity toward BRD9 bromodomain, and significantly inhibited the proliferation of AML cell lines. 10m also showed good metabolic stability, solubility and pharmacokinetic properties. Additionally, oral administration of compounds 10m and 10t exhibited potent anti-tumor efficacy in the MV4-11 xenograft mouse model. The potent, selective, and orally available BRD9 bromodomain inhibitors may address the challenges of weak cellular activity and limited phenotypic efficacy faced by BRD9 inhibitors, and serve as new lead compounds for the development of anticancer agents for the treatment of AML.
{"title":"Key imidazolyl groups that induce phenylalanine flipping enhance the efficacy of oral BRD9 inhibitors for AML treatment","authors":"Zhiming Chen , Cheng Zhang , Hui Shen , Hongrui Xu , Yumin Huang , Ruibo Dong , Xin Tang , Shuang Chai , Junhua Li , Jinxin Xu , Xiaohan Zhang , Yan Zhang , Xishan Wu , Yong Xu","doi":"10.1016/j.apsb.2025.08.006","DOIUrl":"10.1016/j.apsb.2025.08.006","url":null,"abstract":"<div><div>The bromodomain-containing protein 9 (BRD9) is a core subunit of mammalian SWI/SNF chromatin remodeling complex termed ncBAF. BRD9 has emerged as a potential target for anticancer drugs, particularly in the treatment of acute myeloid leukemia (AML). Herein, we reported <strong>10m</strong> (<strong>Y22073</strong>) and <strong>10t</strong> as new BRD9 selective bromodomain inhibitors. Crystallographic studies revealed that the key active imidazolyl group discovered from structure-activity relationship (SAR) can induce Phe163 flipping and significantly enhance the cellular potency of the compounds, making <strong>10m</strong> the first BRD9 selective inhibitor with significant cellular activity against AML cells. We also validated the critical role of imidazolyl groups by modifying existing BRD9 inhibitors. The representative compounds <strong>10m</strong> and <strong>10t</strong> demonstrated potent binding affinity, outstanding selectivity toward BRD9 bromodomain, and significantly inhibited the proliferation of AML cell lines. <strong>10m</strong> also showed good metabolic stability, solubility and pharmacokinetic properties. Additionally, oral administration of compounds <strong>10m</strong> and <strong>10t</strong> exhibited potent anti-tumor efficacy in the MV4-11 xenograft mouse model. The potent, selective, and orally available BRD9 bromodomain inhibitors may address the challenges of weak cellular activity and limited phenotypic efficacy faced by BRD9 inhibitors, and serve as new lead compounds for the development of anticancer agents for the treatment of AML.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6546-6570"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.apsb.2025.09.009
Yu Guo , Yi Song , Hanlin Wang , Yang Lu , Jingyu Zhang , Zheyuan Shen , Weijuan Kan , Yuxian Wang , Haiting Duan , Shuangshuang Geng , Bo Wang , Shaoting Li , Bizhi Li , Xi Chen , Shanshan Pei , Luo Fang , Jia Li , Yubo Zhou , Jinxin Che , Xiaowu Dong
Degrader–antibody conjugates (DACs) represent a promising drug modality for targeting hematological malignancy, but still lack rational design frameworks. Here, we show the strategies of reasonable antibody-degrader compatibility and degradation tail-derived conjugatability through a systematic exploration. Inspired by the success of IKZF1/3 degraders, we sought to explore the potential of cereblon E3 ligase modulators (CELMoDs) in constructing novel conjugates. By combining a modular library with neo-substrate screening and further conjugatable derivation, I034 was identified, a potent CELMoD payload with picomolar degradation activity and antiproliferative effects. Through linker chemistry, I034-based DACs were constructed and demonstrated superior efficacy and safety compared to auristatin-based conjugates both in vitro and in vivo, with the CD38-targeting Dara-VA-I034 achieving complete tumor eradication at low doses. Mechanistic insights revealed distinct positive feedback regulation of CD38 conjugates, highlighting the need for compatibility between payloads and antigens. These results demonstrate that the approach could provide a framework for discovering CELMoD payloads and advancing DACs for treating multiple myeloma and other malignancies.
{"title":"Rational engineering of degradation tail-driven CELMoD–antibody conjugates for precision malignancy therapy","authors":"Yu Guo , Yi Song , Hanlin Wang , Yang Lu , Jingyu Zhang , Zheyuan Shen , Weijuan Kan , Yuxian Wang , Haiting Duan , Shuangshuang Geng , Bo Wang , Shaoting Li , Bizhi Li , Xi Chen , Shanshan Pei , Luo Fang , Jia Li , Yubo Zhou , Jinxin Che , Xiaowu Dong","doi":"10.1016/j.apsb.2025.09.009","DOIUrl":"10.1016/j.apsb.2025.09.009","url":null,"abstract":"<div><div>Degrader–antibody conjugates (DACs) represent a promising drug modality for targeting hematological malignancy, but still lack rational design frameworks. Here, we show the strategies of reasonable antibody-degrader compatibility and degradation tail-derived conjugatability through a systematic exploration. Inspired by the success of IKZF1/3 degraders, we sought to explore the potential of cereblon E3 ligase modulators (CELMoDs) in constructing novel conjugates. By combining a modular library with neo-substrate screening and further conjugatable derivation, <strong>I034</strong> was identified, a potent CELMoD payload with picomolar degradation activity and antiproliferative effects. Through linker chemistry, <strong>I034</strong>-based DACs were constructed and demonstrated superior efficacy and safety compared to auristatin-based conjugates both <em>in vitro</em> and <em>in vivo</em>, with the CD38-targeting Dara-VA-<strong>I034</strong> achieving complete tumor eradication at low doses. Mechanistic insights revealed distinct positive feedback regulation of CD38 conjugates, highlighting the need for compatibility between payloads and antigens. These results demonstrate that the approach could provide a framework for discovering CELMoD payloads and advancing DACs for treating multiple myeloma and other malignancies.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6510-6528"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.apsb.2025.10.030
Yu Zhao , Danyang Zhang , Lin Meng , Siming Shan , Chao Zhang , Zhenzhong Deng , Chao Han , Lingyi Kong
Programmed cell death protein-1/programmed cell death ligand-1 (PD1/PD-L1) blockade has shown promise in cancer therapy but remains limited by low response rates. Recent efforts have explored strategies to enhance immunotherapy efficacy. Histone lysine-specific demethylase 1 (LSD1) inhibition can enhance tumor immune responses by downregulating PD-L1 expression. Furthermore, PD-L1 in tumor cell-derived extracellular vesicles (EVs) contributes to the immunosuppressive tumor microenvironment (TME) and promotes immune evasion. Here, we found that LSD1 inhibition can mediate the rearrangement of PD-L1 on tumor cell surfaces, reduce the secretion of EVs and PD-L1 levels in the TME, and ultimately block the long-range immunosuppression caused by tumor cell-released EVs. Therefore, we developed a TME-targeted synergistic therapy system with a dual mechanism in which anti-PD1 therapy blocks immune checkpoints, and forsythiaside A (FA) acts as an LSD1 inhibitor to regulate EVs secretion. Additionally, CD4+ T cells can directly kill tumor cells by inducing G1/S cell cycle arrest. Ultimately, this system activates the tumor immune response within the TME, effectively inhibiting the growth of non-small cell lung cancer tumors. Our work highlights the signaling role of EVs and the capacity of CD4+ T cells to arrest the cell cycle, offering a new approach to enhance response to anti-PD1/PD-L1 therapy.
{"title":"LSD1 inhibition sensitizes anti-PD1 blockade immunotherapy by inhibiting the long-range attack of tumor-derived extracellular vesicles","authors":"Yu Zhao , Danyang Zhang , Lin Meng , Siming Shan , Chao Zhang , Zhenzhong Deng , Chao Han , Lingyi Kong","doi":"10.1016/j.apsb.2025.10.030","DOIUrl":"10.1016/j.apsb.2025.10.030","url":null,"abstract":"<div><div>Programmed cell death protein-1/programmed cell death ligand-1 (PD1/PD-L1) blockade has shown promise in cancer therapy but remains limited by low response rates. Recent efforts have explored strategies to enhance immunotherapy efficacy. Histone lysine-specific demethylase 1 (LSD1) inhibition can enhance tumor immune responses by downregulating PD-L1 expression. Furthermore, PD-L1 in tumor cell-derived extracellular vesicles (EVs) contributes to the immunosuppressive tumor microenvironment (TME) and promotes immune evasion. Here, we found that LSD1 inhibition can mediate the rearrangement of PD-L1 on tumor cell surfaces, reduce the secretion of EVs and PD-L1 levels in the TME, and ultimately block the long-range immunosuppression caused by tumor cell-released EVs. Therefore, we developed a TME-targeted synergistic therapy system with a dual mechanism in which anti-PD1 therapy blocks immune checkpoints, and forsythiaside A (FA) acts as an LSD1 inhibitor to regulate EVs secretion. Additionally, CD4<sup>+</sup> T cells can directly kill tumor cells by inducing G1/S cell cycle arrest. Ultimately, this system activates the tumor immune response within the TME, effectively inhibiting the growth of non-small cell lung cancer tumors. Our work highlights the signaling role of EVs and the capacity of CD4<sup>+</sup> T cells to arrest the cell cycle, offering a new approach to enhance response to anti-PD1/PD-L1 therapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 12","pages":"Pages 6657-6680"},"PeriodicalIF":14.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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