Pub Date : 2026-10-01Epub Date: 2026-06-24DOI: 10.1016/j.apsb.2026.06.042
Xingjun Li, Tao Yang, Hui Huang, Yalan Ma, Lu Liu, Qingqing Li, Naixia Zhang, Zhizhen Hui, Yazhou Li, Fang Bai, Qiangqiang Chen, Jiang Wang, Chen Zhou, Hu Zhou, Wei Tang, Hong Liu
Sepsis is a leading cause of mortality among patients in intensive care units (ICUs), with no specific treatments for sepsis available in clinical practice. In this study, we report the discovery of compound A12, a tanshinone derivative featuring a covalent warhead, which demonstrates potent anti-inflammatory effects both in vitro and in vivo. In a lipopolysaccharide-induced mouse model of endotoxemia and acute systemic inflammation, A12 significantly reduces levels of TNF-α, IL-6, and IL-12. Distinct from current anti-inflammatory small molecules, A12 presents a unique mechanism, covalently binding to DNAJC9, thereby modulating the HSP complex and inhibiting the downstream inflammatory response. This work represents the first application of covalent drug design principles to the structural modification of the natural product tanshinone, and reveals the previously unrecognized role of DNAJC9 in inflammatory diseases, offering a novel therapeutic target for management of sepsis-associated acute systemic inflammation.
{"title":"Discovery of a potent covalent inhibitor for the treatment of sepsis targeting DNAJC9: Identification of a druggable target for inflammation","authors":"Xingjun Li, Tao Yang, Hui Huang, Yalan Ma, Lu Liu, Qingqing Li, Naixia Zhang, Zhizhen Hui, Yazhou Li, Fang Bai, Qiangqiang Chen, Jiang Wang, Chen Zhou, Hu Zhou, Wei Tang, Hong Liu","doi":"10.1016/j.apsb.2026.06.042","DOIUrl":"10.1016/j.apsb.2026.06.042","url":null,"abstract":"<div><div>Sepsis is a leading cause of mortality among patients in intensive care units (ICUs), with no specific treatments for sepsis available in clinical practice. In this study, we report the discovery of compound <strong>A12</strong>, a tanshinone derivative featuring a covalent warhead, which demonstrates potent anti-inflammatory effects both <em>in vitro</em> and <em>in vivo</em>. In a lipopolysaccharide-induced mouse model of endotoxemia and acute systemic inflammation, <strong>A12</strong> significantly reduces levels of TNF-<em>α</em>, IL-6, and IL-12. Distinct from current anti-inflammatory small molecules, <strong>A12</strong> presents a unique mechanism, covalently binding to DNAJC9, thereby modulating the HSP complex and inhibiting the downstream inflammatory response. This work represents the first application of covalent drug design principles to the structural modification of the natural product tanshinone, and reveals the previously unrecognized role of DNAJC9 in inflammatory diseases, offering a novel therapeutic target for management of sepsis-associated acute systemic inflammation.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 6892-6904"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149204675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-01Epub Date: 2026-08-03DOI: 10.1016/j.apsb.2026.07.055
Fangfang Wang, Sora Jin, Franklin Mayca Pozo, Danmei Tian, Xiyang Tang, Yi Dai, Xinsheng Yao, Jinshan Tang, Youwei Zhang
{"title":"Author correction to “Chemical screen identifies shikonin as a broad DNA damage response inhibitor that enhances chemotherapy through inhibiting ATM and ATR” [Acta Pharm Sin B 12 (2022) 1339–1350]","authors":"Fangfang Wang, Sora Jin, Franklin Mayca Pozo, Danmei Tian, Xiyang Tang, Yi Dai, Xinsheng Yao, Jinshan Tang, Youwei Zhang","doi":"10.1016/j.apsb.2026.07.055","DOIUrl":"10.1016/j.apsb.2026.07.055","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 7096-7097"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149205248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-01Epub Date: 2026-05-20DOI: 10.1016/j.apsb.2026.05.017
Qiangyun Ai, Huina Hu, Kaixiong Ma, Qingxing Wang, Shenglin Huang, Yongzhi Lu, Nan Qi, Jinsai Shang, Ruikun Du, Shaobo Wang
Nucleoside analogues are among the most promising broad-spectrum antiviral agents. We developed a high-throughput synergistic screening system to identify US Food and Drug Administration-approved drugs that enhance the effectiveness of nucleoside analogues. Unlike conventional combination approaches, this strategy does not require boost agents to have direct antiviral activity; instead, they can enhance antiviral agent’s effect through novel synergistic mechanisms. We identified mycophenolate mofetil (MMF), which significantly boosts ribavirin’s (RBV) antiviral efficacy against influenza A virus, even at concentrations where MMF alone shows minimal activity. MMF enhances RBV by inhibiting IMPDH (inosine-5′-monophosphate dehydrogenase) and reducing cellular GTP levels, potentially increasing RBV incorporation and its antiviral potency. This mechanism was confirmed by adding exogenous GTP, which reversed the synergy. In a mouse model, MMF also enhanced RBV’s effectiveness against PR8 in vivo. Moreover, MMF showed synergistic effects against other influenza subtypes and RNA viruses including ZIKV and HCoV-OC43, demonstrating the potential wide applicability of this strategy. Our study introduces a new screening system and identifies novel RBV combinations, offering a promising approach for developing effective broad-spectrum antiviral combinations against emerging viral threats.
{"title":"Identification of FDA-approved IMPDH inhibitors boosting the broad-spectrum antiviral potential of ribavirin through depleting cellular GTP pool","authors":"Qiangyun Ai, Huina Hu, Kaixiong Ma, Qingxing Wang, Shenglin Huang, Yongzhi Lu, Nan Qi, Jinsai Shang, Ruikun Du, Shaobo Wang","doi":"10.1016/j.apsb.2026.05.017","DOIUrl":"10.1016/j.apsb.2026.05.017","url":null,"abstract":"<div><div>Nucleoside analogues are among the most promising broad-spectrum antiviral agents. We developed a high-throughput synergistic screening system to identify US Food and Drug Administration-approved drugs that enhance the effectiveness of nucleoside analogues. Unlike conventional combination approaches, this strategy does not require boost agents to have direct antiviral activity; instead, they can enhance antiviral agent’s effect through novel synergistic mechanisms. We identified mycophenolate mofetil (MMF), which significantly boosts ribavirin’s (RBV) antiviral efficacy against influenza A virus, even at concentrations where MMF alone shows minimal activity. MMF enhances RBV by inhibiting IMPDH (inosine-5′-monophosphate dehydrogenase) and reducing cellular GTP levels, potentially increasing RBV incorporation and its antiviral potency. This mechanism was confirmed by adding exogenous GTP, which reversed the synergy. In a mouse model, MMF also enhanced RBV’s effectiveness against PR8 <em>in vivo</em>. Moreover, MMF showed synergistic effects against other influenza subtypes and RNA viruses including ZIKV and HCoV-OC43, demonstrating the potential wide applicability of this strategy. Our study introduces a new screening system and identifies novel RBV combinations, offering a promising approach for developing effective broad-spectrum antiviral combinations against emerging viral threats.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 6875-6891"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149205277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Redox imbalance has become an important factor in rheumatoid arthritis (RA) progression, previous studies showed selenium nanozymes (Se NPs) effectively treated RA by restoring redox. However, the process of Se NPs regulates RA, especially the mechanism of Se NPs activates selenoproteins in inhibiting inflammation remains unclear. Herein, the redox imbalance in RA patients was first analyzed, and selenoproteins associated with macrophage inflammation were identified via mRNA profiling. Subsequently, the synthesized Se NPs with glutathione peroxidase (GPX)-like activity as a supplement, and it was found that Se NPs specially upregulate selenoproteins in macrophages applied to in vitro and in vivo models, furthermore combined with GPX-like activity, Se NPs quickly eliminated reactive oxygen and nitrogen species (RONS), restored redox homeostasis in RA, and alleviated symptoms of RA by effectively inhibiting macrophage inflammation. The mechanistic study showed that Se NPs effectively prevent mitochondrial and nDNA damage by specifically activating selenoproteins, blocking the interaction between DNA and cyclic GMP–AMP synthase (cGAS), and restraining the activation of cGAS–stimulator of interferon genes (STING) and nuclear factor kappa-B (NF-κB) pathway, thus effectively suppressing macrophage inflammation and treating RA. Therefore, this study reveals the mechanism by which Se NPs inhibit macrophage inflammation, providing a new potential therapeutic target for treating inflammatory diseases.
氧化还原失衡已成为类风湿关节炎（RA）进展的重要因素，已有研究表明硒纳米酶（Se NPs）通过恢复氧化还原能有效治疗RA。然而，Se NPs调控RA的过程，特别是Se NPs激活硒蛋白抑制炎症的机制尚不清楚。本文首先分析了RA患者的氧化还原失衡，并通过mRNA谱分析鉴定了与巨噬细胞炎症相关的硒蛋白。随后，将合成的具有谷胱甘肽过氧化物酶（GPX）样活性的Se NPs作为补充，应用于体外和体内模型，发现Se NPs特异性上调巨噬细胞中的硒蛋白，并与GPX样活性结合，通过有效抑制巨噬细胞炎症，迅速消除活性氧和活性氮（RONS），恢复RA的氧化还原平衡，缓解RA症状。机制研究表明Se NPs通过特异性激活硒蛋白，阻断DNA与环GMP-AMP合成酶（cGAS）的相互作用，抑制干扰素基因（STING）和核因子κ b （NF-κB）通路的激活，有效预防线粒体和nDNA损伤，从而有效抑制巨噬细胞炎症，治疗RA。因此，本研究揭示了Se NPs抑制巨噬细胞炎症的机制，为治疗炎症性疾病提供了新的潜在治疗靶点。
{"title":"Selenium nanozymes effectively treat rheumatoid arthritis by specifically activating selenoproteins to block oxidative damage and cGAS–STING signaling pathway","authors":"Yang Yang, Yonglan Yang, Wenguan Huang, Xiaoyan Zhong, Shuyang Chen, Zhixiang Huang, Xinghuan Xie, Guanqun Yi, Tianwang Li, Xu Chen","doi":"10.1016/j.apsb.2026.06.023","DOIUrl":"10.1016/j.apsb.2026.06.023","url":null,"abstract":"<div><div>Redox imbalance has become an important factor in rheumatoid arthritis (RA) progression, previous studies showed selenium nanozymes (Se NPs) effectively treated RA by restoring redox. However, the process of Se NPs regulates RA, especially the mechanism of Se NPs activates selenoproteins in inhibiting inflammation remains unclear. Herein, the redox imbalance in RA patients was first analyzed, and selenoproteins associated with macrophage inflammation were identified <em>via</em> mRNA profiling. Subsequently, the synthesized Se NPs with glutathione peroxidase (GPX)-like activity as a supplement, and it was found that Se NPs specially upregulate selenoproteins in macrophages applied to <em>in vitro</em> and <em>in vivo</em> models, furthermore combined with GPX-like activity, Se NPs quickly eliminated reactive oxygen and nitrogen species (RONS), restored redox homeostasis in RA, and alleviated symptoms of RA by effectively inhibiting macrophage inflammation. The mechanistic study showed that Se NPs effectively prevent mitochondrial and nDNA damage by specifically activating selenoproteins, blocking the interaction between DNA and cyclic GMP–AMP synthase (cGAS), and restraining the activation of cGAS–stimulator of interferon genes (STING) and nuclear factor kappa-B (NF-<em>κ</em>B) pathway, thus effectively suppressing macrophage inflammation and treating RA. Therefore, this study reveals the mechanism by which Se NPs inhibit macrophage inflammation, providing a new potential therapeutic target for treating inflammatory diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 6338-6359"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149214233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-01Epub Date: 2026-06-18DOI: 10.1016/j.apsb.2026.06.029
Yafei Yang, Furong Zhang, Zhuang Peng, Yafei Wu, Ling Li, Zixia Shen, Qifa Ye, Jiang Yue, Shufang Na
Lean metabolic dysfunction-associated steatotic liver disease (MASLD), defined as hepatic steatosis in individuals with normal BMI (<25 kg/m2 in non-Asians; <23 kg/m2 in Asians), is a clinically paradoxical phenotype in which patients face risks of progressive fibrosis, cardiovascular events, and liver-related mortality comparable to or exceeding obese counterparts. Visceral adiposity, dietary stressors, cholesterol overload, and genetic susceptibility involving PNPLA3 variants and PPARA polymorphisms synergistically disrupt hepatic lipid homeostasis. At the core of this dysregulation lies peroxisome proliferator-activated receptor alpha (PPARα), a master transcriptional regulator of hepatic fatty acid oxidation, ketogenesis, and anti-inflammatory signaling. PPARα suppression aries through convergent mechanisms, including aging-related RAGE signaling, fructose-mediated epigenetic silencing, gut‒liver axis disruption, and lipotoxicity, operating independently of systemic obesity. This review demonstrates that: (1) impaired PPARα activity underlies lean MASLD pathogenesis through transcriptional, epigenetic, and post-translational suppression; (2) synthetic PPARα agonists show limited applicability in this metabolically fragile population; and (3) natural product-derived modulators engage PPARα alongside FXR and LXR networks to restore metabolic balance. The PPARα–FGF21–ketogenesis axis and nuclear receptor crosstalk provide the mechanistic rationale for network-level therapeutic approaches. We advocate for spatially selective hepatic PPARα reactivation guided by lean-specific biomarker and genotype-stratified trial design.
{"title":"Emerging insights into PPARα′s role in lean metabolic dysfunction-associated steatotic liver disease: Implications for targeted therapies","authors":"Yafei Yang, Furong Zhang, Zhuang Peng, Yafei Wu, Ling Li, Zixia Shen, Qifa Ye, Jiang Yue, Shufang Na","doi":"10.1016/j.apsb.2026.06.029","DOIUrl":"10.1016/j.apsb.2026.06.029","url":null,"abstract":"<div><div>Lean metabolic dysfunction-associated steatotic liver disease (MASLD), defined as hepatic steatosis in individuals with normal BMI (<25 kg/m<sup>2</sup> in non-Asians; <23 kg/m<sup>2</sup> in Asians), is a clinically paradoxical phenotype in which patients face risks of progressive fibrosis, cardiovascular events, and liver-related mortality comparable to or exceeding obese counterparts. Visceral adiposity, dietary stressors, cholesterol overload, and genetic susceptibility involving <em>PNPLA3</em> variants and <em>PPARA</em> polymorphisms synergistically disrupt hepatic lipid homeostasis. At the core of this dysregulation lies peroxisome proliferator-activated receptor alpha (PPAR<em>α</em>), a master transcriptional regulator of hepatic fatty acid oxidation, ketogenesis, and anti-inflammatory signaling. PPAR<em>α</em> suppression aries through convergent mechanisms, including aging-related RAGE signaling, fructose-mediated epigenetic silencing, gut‒liver axis disruption, and lipotoxicity, operating independently of systemic obesity. This review demonstrates that: (1) impaired PPAR<em>α</em> activity underlies lean MASLD pathogenesis through transcriptional, epigenetic, and post-translational suppression; (2) synthetic PPAR<em>α</em> agonists show limited applicability in this metabolically fragile population; and (3) natural product-derived modulators engage PPAR<em>α</em> alongside FXR and LXR networks to restore metabolic balance. The PPAR<em>α</em>–FGF21–ketogenesis axis and nuclear receptor crosstalk provide the mechanistic rationale for network-level therapeutic approaches. We advocate for spatially selective hepatic PPAR<em>α</em> reactivation guided by lean-specific biomarker and genotype-stratified trial design.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 6462-6506"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149205204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-01Epub Date: 2026-03-10DOI: 10.1016/j.apsb.2026.03.007
Jiatong Liu, Wenfan Chen, Xiufeng Li, Yuanyuan Luo, Qiaomin Li, Wenbin Zhao, Qiaojun He, Su Zeng, Zhan Zhou, Sheng Cai
The emergence of SARS-CoV-2 has led to a global pandemic, causing unprecedented disruption to health systems and economies worldwide, calling for an urgent imperative for precise and sensitive diagnostic method. To address this, a novel detection method, termed antibody‒nucleic acid conjugate linked immunosorbent assay (ANCLISA), was designed for the ultra-sensitive detection of the receptor binding domain (RBD) of SARS-CoV-2, which play a pivotal role in the diagnosis of COVID-19. Leveraging the Alphafold 2 model for simulating antibody‒antigen complexes and the ΔΔG predictor model for forecasting the binding free energy of antigen‒antibody complex, we successfully identified the high-affinity antibody TB1. Through the utilization of succinimidyl 4-[N-maleimidomethyl] cyclohexane-1-carboxylate (SMCC) for antibody‒nucleic acid conjugation and the integration of the hybridization chain reaction (HCR) for signal amplification within the system, we have established an ultra-sensitive approach for the SARS-CoV-2 Delta variant detection. The proposed immunoassay provided exhibited a linear detection range spanning 11 fg/mL to 11 ng/mL, achieving a limit of detection (LOD) of 1.48 fg/mL. Our innovative approach represents a significant stride in enabling precise and ultra-sensitive detection of SARS-CoV-2, thereby holding promise for enhancing diagnostic capabilities in the ongoing global battle against the pandemic.
{"title":"Ultra-sensitive detection of receptor binding domain of SARS-CoV-2 based on artificial intelligence assisted antibody selection and antibody‒nucleic acid conjugation signal amplification","authors":"Jiatong Liu, Wenfan Chen, Xiufeng Li, Yuanyuan Luo, Qiaomin Li, Wenbin Zhao, Qiaojun He, Su Zeng, Zhan Zhou, Sheng Cai","doi":"10.1016/j.apsb.2026.03.007","DOIUrl":"10.1016/j.apsb.2026.03.007","url":null,"abstract":"<div><div>The emergence of SARS-CoV-2 has led to a global pandemic, causing unprecedented disruption to health systems and economies worldwide, calling for an urgent imperative for precise and sensitive diagnostic method. To address this, a novel detection method, termed antibody‒nucleic acid conjugate linked immunosorbent assay (ANCLISA), was designed for the ultra-sensitive detection of the receptor binding domain (RBD) of SARS-CoV-2, which play a pivotal role in the diagnosis of COVID-19. Leveraging the Alphafold 2 model for simulating antibody‒antigen complexes and the ΔΔ<em>G</em> predictor model for forecasting the binding free energy of antigen‒antibody complex, we successfully identified the high-affinity antibody TB1. Through the utilization of succinimidyl 4-[<em>N</em>-maleimidomethyl] cyclohexane-1-carboxylate (SMCC) for antibody‒nucleic acid conjugation and the integration of the hybridization chain reaction (HCR) for signal amplification within the system, we have established an ultra-sensitive approach for the SARS-CoV-2 Delta variant detection. The proposed immunoassay provided exhibited a linear detection range spanning 11 fg/mL to 11 ng/mL, achieving a limit of detection (LOD) of 1.48 fg/mL. Our innovative approach represents a significant stride in enabling precise and ultra-sensitive detection of SARS-CoV-2, thereby holding promise for enhancing diagnostic capabilities in the ongoing global battle against the pandemic.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 7075-7085"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149205206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Critical illnesses such as sepsis and acute respiratory distress syndrome (ARDS) evolve rapidly and are dominated by systemic inflammatory dysregulation, oxidative stress, and abrupt microenvironmental remodeling, which collectively narrow the therapeutic window and amplify treatment-related toxicity. Conventional pharmacotherapy is often limited by non-selective biodistribution, insufficient lesion exposure, and dose-limiting adverse effects. Intelligent nano-delivery systems (INDS) address these barriers by coupling pathological cues (e.g., pH gradients, redox/ROS imbalance, and disease-associated enzymes) to defined carrier-state transitions, thereby enabling lesion-confined activation, controlled bioavailability, and, in selected designs, real-time readouts. In this review, we summarize the design logic of stimulus-responsive and targeting modules, and critically discuss how they translate endogenous signals into payload release or functional actuation in representative critical-illness settings. We further highlight emerging directions, including self-adaptive multi-input gating and biomimetic interfaces, and discuss key translational constraints (manufacturability, safety, and reproducibility) that must be addressed to advance INDS toward critical-care practice.
{"title":"Intelligent nano delivery systems: Classification, stimuli-responsive mechanisms, and therapeutic applications in critical illnesses","authors":"Mengxin Zhao, Baofeng Guo, Quanhao Wang, Mei Yang, Jiaying Yang, Yueyang Liang, Wei Jiang, Ling Zhang","doi":"10.1016/j.apsb.2026.06.015","DOIUrl":"10.1016/j.apsb.2026.06.015","url":null,"abstract":"<div><div>Critical illnesses such as sepsis and acute respiratory distress syndrome (ARDS) evolve rapidly and are dominated by systemic inflammatory dysregulation, oxidative stress, and abrupt microenvironmental remodeling, which collectively narrow the therapeutic window and amplify treatment-related toxicity. Conventional pharmacotherapy is often limited by non-selective biodistribution, insufficient lesion exposure, and dose-limiting adverse effects. Intelligent nano-delivery systems (INDS) address these barriers by coupling pathological cues (<em>e.g.</em>, pH gradients, redox/ROS imbalance, and disease-associated enzymes) to defined carrier-state transitions, thereby enabling lesion-confined activation, controlled bioavailability, and, in selected designs, real-time readouts. In this review, we summarize the design logic of stimulus-responsive and targeting modules, and critically discuss how they translate endogenous signals into payload release or functional actuation in representative critical-illness settings. We further highlight emerging directions, including self-adaptive multi-input gating and biomimetic interfaces, and discuss key translational constraints (manufacturability, safety, and reproducibility) that must be addressed to advance INDS toward critical-care practice.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 6309-6337"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149205207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-01Epub Date: 2026-02-19DOI: 10.1016/j.apsb.2026.02.013
Luyao Yu, Yingxia Guo, Tonghe Liu, Yunlong Sheng, Meichen Liu, Ning Zhang, Jiye Tian, Chunpeng Feng, Meiyun Shi, Lei Yin
Paclitaxel (PTX) has poor aqueous solubility and vehicle-related toxicity. Polymeric micelles (PMs) can improve solubility and leverage the enhanced permeability and retention (EPR) effect for tumor targeting. However, a comprehensive understanding of their in vivo fate remains limited, due to the inability to distinguish between encapsulated and released drug. We developed a novel method integrating stable isotope tracing, ultrafiltration, and ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) to quantify free, released, and total PTX, the polymeric carriers methoxy-poly(ethylene glycol) (molecular weight ∼2000 Da) (mPEG2K) and methoxy-poly(ethylene glycol)-block-poly(d,l-lactic acid) (mPEG block MW ∼2000 Da, PLA block MW ∼2000 Da) (mPEG2K–PLA2K) in rats following administration of PTX injection and paclitaxel-loaded polymeric micelles (PTX-PMs). PTX-PMs significantly altered the pharmacokinetics, reducing the initial dose–normalized initial plasma concentration (C0/Dose) of free PTX to 27.0% of that from the injection. Altered tissue distribution was observed, with high accumulation in reticuloendothelial system (RES) organs and more complete clearance by 48 h. Excretion studies revealed a substantially higher cumulative fecal excretion of PTX after PTX-PMs administration, while the polymer carrier was predominantly excreted renally as mPEG2K. These findings provide critical insights into the in vivo disposition of PTX nanoformulations, supporting the rational design of PMs-based delivery systems.
{"title":"In vivo fate mapping of a paclitaxel-loaded polymeric micelle and its components","authors":"Luyao Yu, Yingxia Guo, Tonghe Liu, Yunlong Sheng, Meichen Liu, Ning Zhang, Jiye Tian, Chunpeng Feng, Meiyun Shi, Lei Yin","doi":"10.1016/j.apsb.2026.02.013","DOIUrl":"10.1016/j.apsb.2026.02.013","url":null,"abstract":"<div><div>Paclitaxel (PTX) has poor aqueous solubility and vehicle-related toxicity. Polymeric micelles (PMs) can improve solubility and leverage the enhanced permeability and retention (EPR) effect for tumor targeting. However, a comprehensive understanding of their <em>in vivo</em> fate remains limited, due to the inability to distinguish between encapsulated and released drug. We developed a novel method integrating stable isotope tracing, ultrafiltration, and ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) to quantify free, released, and total PTX, the polymeric carriers methoxy-poly(ethylene glycol) (molecular weight ∼2000 Da) (mPEG2K) and methoxy-poly(ethylene glycol)-<em>block</em>-poly(<span>d</span>,<span>l</span>-lactic acid) (mPEG block MW ∼2000 Da, PLA block MW ∼2000 Da) (mPEG2K–PLA2K) in rats following administration of PTX injection and paclitaxel-loaded polymeric micelles (PTX-PMs). PTX-PMs significantly altered the pharmacokinetics, reducing the initial dose–normalized initial plasma concentration (<em>C</em><sub>0</sub>/Dose) of free PTX to 27.0% of that from the injection. Altered tissue distribution was observed, with high accumulation in reticuloendothelial system (RES) organs and more complete clearance by 48 h. Excretion studies revealed a substantially higher cumulative fecal excretion of PTX after PTX-PMs administration, while the polymer carrier was predominantly excreted renally as mPEG2K. These findings provide critical insights into the <em>in vivo</em> disposition of PTX nanoformulations, supporting the rational design of PMs-based delivery systems.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 7019-7036"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149205282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-01Epub Date: 2026-08-08DOI: 10.1016/j.apsb.2026.08.005
Hongmei Zheng, Haipeng Cheng, Namei Li, Jing Cai
Lysosomes were once regarded merely as the cellular “waste disposal” system, but are now widely recognized as pivotal hubs for regulating intracellular homeostasis and have emerged as promising therapeutic targets in cancer treatment. This review systematically explores the interplay between nanomaterials and lysosomal function, focusing particularly on how to leverage this interaction to enhance antitumor efficacy. First, we outline the mechanisms by which nanomaterials modulate lysosomal activity. Next, we review the main antitumor pathways used by lysosome-targeted nanomaterials, such as inhibiting autophagic flux, activating programmed cell death pathways (including cuproptosis, ferroptosis, apoptosis, and pyroptosis), and remodeling the immunosuppressive tumor microenvironment. We also analyze various strategies for synergistic enhancement, such as metabolic intervention and stimuli-responsive combination therapies (such as light-, ultrasound- or ROS-activated), as well as lysosome-targeted approaches for improving conventional chemotherapy and radiotherapy. In conclusion, this review provides a comprehensive overview of current lysosome-targeted nanomedicine research and outlines future directions for translating these strategies into clinical applications.
{"title":"Lysosome-targeted nanomaterials for advanced cancer therapy: Overcoming resistance, activating immunity and amplifying therapeutic synergy","authors":"Hongmei Zheng, Haipeng Cheng, Namei Li, Jing Cai","doi":"10.1016/j.apsb.2026.08.005","DOIUrl":"10.1016/j.apsb.2026.08.005","url":null,"abstract":"<div><div>Lysosomes were once regarded merely as the cellular “waste disposal” system, but are now widely recognized as pivotal hubs for regulating intracellular homeostasis and have emerged as promising therapeutic targets in cancer treatment. This review systematically explores the interplay between nanomaterials and lysosomal function, focusing particularly on how to leverage this interaction to enhance antitumor efficacy. First, we outline the mechanisms by which nanomaterials modulate lysosomal activity. Next, we review the main antitumor pathways used by lysosome-targeted nanomaterials, such as inhibiting autophagic flux, activating programmed cell death pathways (including cuproptosis, ferroptosis, apoptosis, and pyroptosis), and remodeling the immunosuppressive tumor microenvironment. We also analyze various strategies for synergistic enhancement, such as metabolic intervention and stimuli-responsive combination therapies (such as light-, ultrasound- or ROS-activated), as well as lysosome-targeted approaches for improving conventional chemotherapy and radiotherapy. In conclusion, this review provides a comprehensive overview of current lysosome-targeted nanomedicine research and outlines future directions for translating these strategies into clinical applications.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 6606-6631"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149204642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-10-01Epub Date: 2026-06-08DOI: 10.1016/j.apsb.2026.06.006
Gaeun Ma, Yun-Hwa Jeong, Yeonsu Ryu, Jae-Hyeon Lee, Seong-Bin Yang, Byeong-Kook Hwang, Jeong Uk Choi, Jooho Park
Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a potential therapeutic strategy for cancer. However, intrinsic resistance, off-target toxicity, and poor redox efficiency limit the effectiveness of existing ferroptosis-inducing platforms. This study reports novel heparin-derived metal coordination nanoparticles (HDMC NP) that leverage catechol–metal–drug coordination chemistry to enhance ferroptosis and immunogenic cell death (ICD). In this self-assembled supramolecular system, doxorubicin (DOX) directly coordinates to Fe3+ centers established by catechol–Fe3+ interactions on the heparin backbone, forming a stable HDMC NP with high drug-loading efficiency. This coordination not only stabilizes the complex under neutral conditions but also triggers disassembly in response to pH changes in the tumor microenvironment. Notably, the DOX–Fe3+ pairing supports sustained redox activity, amplifying ROS production and ferroptotic stress in a coordination-dependent manner beyond the effect of either component alone. In animal models, HDMC NP suppresses tumor growth by inducing both ferroptosis and ICD, characterized by calreticulin exposure and CD8+ T cell infiltration. Collectively, this platform provides a redox-active nanotherapeutic based on coordination-defined assembly with potential for broad applications in metal-ion modulated diseases.
{"title":"Double coordination-driven Fe–DOX synergy enhances ferroptosis and immunogenic cancer therapy","authors":"Gaeun Ma, Yun-Hwa Jeong, Yeonsu Ryu, Jae-Hyeon Lee, Seong-Bin Yang, Byeong-Kook Hwang, Jeong Uk Choi, Jooho Park","doi":"10.1016/j.apsb.2026.06.006","DOIUrl":"10.1016/j.apsb.2026.06.006","url":null,"abstract":"<div><div>Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a potential therapeutic strategy for cancer. However, intrinsic resistance, off-target toxicity, and poor redox efficiency limit the effectiveness of existing ferroptosis-inducing platforms. This study reports novel heparin-derived metal coordination nanoparticles (HDMC NP) that leverage catechol–metal–drug coordination chemistry to enhance ferroptosis and immunogenic cell death (ICD). In this self-assembled supramolecular system, doxorubicin (DOX) directly coordinates to Fe<sup>3+</sup> centers established by catechol–Fe<sup>3+</sup> interactions on the heparin backbone, forming a stable HDMC NP with high drug-loading efficiency. This coordination not only stabilizes the complex under neutral conditions but also triggers disassembly in response to pH changes in the tumor microenvironment. Notably, the DOX–Fe<sup>3+</sup> pairing supports sustained redox activity, amplifying ROS production and ferroptotic stress in a coordination-dependent manner beyond the effect of either component alone. In animal models, HDMC NP suppresses tumor growth by inducing both ferroptosis and ICD, characterized by calreticulin exposure and CD8<sup>+</sup> T cell infiltration. Collectively, this platform provides a redox-active nanotherapeutic based on coordination-defined assembly with potential for broad applications in metal-ion modulated diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 6958-6983"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149204678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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