Acta Pharmaceutica Sinica. B最新文献_第10页

Ferroptosis meets cancer immunotherapy: Overcoming the crosstalk challenges through advanced drug delivery strategies 铁下垂与癌症免疫治疗：通过先进的药物递送策略克服串扰挑战

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 Epub Date: 2025-10-03 DOI: 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.

铁下垂诱导与肿瘤免疫治疗的结合已成为一种很有前途的肿瘤治疗方法，提供了克服治疗耐药和肿瘤异质性的双重机制。然而，肿瘤微环境中铁下垂过程与免疫调节之间的动态和复杂的串扰带来了机遇和挑战。通过诱导肿瘤组织脂质过氧化，嗜铁性肿瘤细胞死亡可刺激免疫原性。然而，过度的脂质过氧化可能会矛盾地损害多种免疫细胞的功能，从而在治疗策略中提出串扰挑战。为了解决这些串扰挑战，人们提出了几种先进的药物递送策略，如免疫刺激活性药物成分共递送、肿瘤靶向递送和刺激响应递送。这些药物递送策略通过协同增强恶性细胞的铁下垂诱导，同时减轻免疫毒性，甚至增强抗肿瘤免疫，显示出双重治疗效果。这篇综述提供了铁下垂和肿瘤免疫之间的相互作用的详细见解，以及三种递送策略的指导概述。深入分析了当前的障碍和翻译潜力，为未来的研究提供了有价值的观点。

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引用次数: 0

Injectable hydrogel-mediated co-delivery of oncolytic adenovirus and melphalan for retinoblastoma control and vision preservation 可注射水凝胶介导的溶瘤腺病毒和melphalan共同递送用于视网膜母细胞瘤的控制和视力保护

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 Epub Date: 2025-09-20 DOI: 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.

视网膜母细胞瘤（RB）是儿童最常见的原发性眼部恶性肿瘤，起源于发育中的视网膜。虽然高剂量的局部化疗改善了肿瘤控制，但对视网膜毒性和化疗耐药性发展的关注仍然很重要。溶瘤腺病毒（OA）是治疗RB的一种很有前途的方法，但快速清除往往限制了其治疗效果。在这项研究中，我们设计了一种源自人腺病毒5 （Ad5）的基因修饰OA，旨在选择性地靶向和裂解RB细胞。OA与低剂量美伐兰联合使用显示出增强的抗肿瘤作用，同时将视网膜毒性降至最低。体外和体内实验表明，美伐兰可显著增强OA的抗肿瘤作用，延长眼存活时间。更重要的是，我们开发了一种基于胶原蛋白和醛修饰环糊精共价偶联的生物相容性可注射水凝胶递送系统，有效提高了美法兰的负载效率，实现了OA和美法兰的持续共递送。小鼠RB肿瘤模型证实，该水凝胶系统（OA-Mel@CCA）实现了两种治疗药物的局部和持续递送，有效控制肿瘤生长并防止脑转移。此外，OA-Mel@CCA处理小鼠的视网膜结构和功能得到了明显的保存，没有观察到视网膜毒性。这些发现表明，可注射的基于水凝胶的美法兰和溶瘤腺病毒共同递送可能是治疗RB的一种有希望的策略。

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引用次数: 0

Probiotic living microneedles designed by interbacterial competition for accelerated infected wound healing 细菌间竞争设计的益生菌活微针加速感染伤口愈合

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 Epub Date: 2025-10-27 DOI: 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.

益生菌疗法通过抑制病原体和免疫调节为慢性感染伤口治疗提供了一种很有前途的策略。然而，由于其在富含病原体的生态位中的竞争力较弱，以及穿透生物膜屏障的能力较差，其效果仍然受到限制。受细菌竞争相互作用的启发，我们开发了一种多功能微针（MN）平台来克服这些限制。罗伊氏乳杆菌（Lactobacillus reuteri, Lr）被聚赖氨酸修饰的金属酚网络（mpn）包被阿霉素（DOX），得到DOX@MPN - PLL@Lr （DMP@Lr）。将工程益生菌掺入富营养液的可溶性MNs中，保证了优良的微针性能和益生菌功能。该设计利用MPN的多功能性，通过光热辅助的细菌杀灭和近红外（NIR）促进的抗生素释放来减少早期致病负担，从而增强益生菌的竞争力。与此同时，MNs在物理上破坏生物膜，以便精确地递送到深层感染部位。在体外，DMP@Lr达到了99.9% （5.5 log）的杀菌效率，其MNs的生物膜清除率比空白MNs高1.4倍。在体内，一个DMP@Lr MN贴片促进93.9%的伤口愈合，显示出强大的抗菌活性和加速愈合。这项研究提出了一种创新的，可翻译的益生菌为基础的MN治疗慢性感染伤口的有效治疗。

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引用次数: 0

The cytoskeletal protein smoothelin maintains homologous recombination repair by stabilizing RAD51 in an HUWE1-dependent manner in colorectal cancer 细胞骨架蛋白smoothelin通过稳定结直肠癌中依赖于huwe1的RAD51来维持同源重组修复

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 Epub Date: 2025-10-01 DOI: 10.1016/j.apsb.2025.09.042

Wei Xu , Minmin Shen , Junjie Ma , Chuanlin Peng , Shanshan Wu , Xinxin Yang , Jiahe Wu , Youyou Yan , Nengming Lin , Jianqing Gao , Bo Zhang

Dysregulation of cytoskeletal proteins has been found in response to DNA damage stress, yet the functional role of cytoskeletal proteins in DNA repair remained unexplored. Here, we found that DNA-damaging agents induced substantial upregulation of smooth muscle-specific cytoskeletal protein smoothelin (SMTN) in colorectal cancer (CRC) cells. Silencing SMTN abrogated G2/M arrest, exacerbated DNA damage, and markedly enhanced the chemosensitivity of CRC cells to various DNA-damaging agents. Notably, SMTN could rapidly accumulate at DNA damage sites within 1 min after laser irradiation, which was indispensable for the initiation of homologous recombination (HR) repair. Mechanistically, SMTN stabilized RAD51 by disrupting its interaction with its E3 ubiquitin ligase HUWE1, thereby maintaining the process of HR repair. To explore the therapeutic role of SMTN, customized cell membrane infused biomimetic liposomes were constructed to ensure rapid delivery of SMTN siRNA specifically into HCT-116 cells, yielding significantly enhanced anti-cancer effects of irinotecan and fuzuloparib both in vitro and in vivo. To summarize, our findings revealed a novel function of SMTN in DNA damage repair and provided a therapeutic strategy of targeting SMTN to enhance the efficacy of DNA damage agents.

细胞骨架蛋白的失调已被发现在DNA损伤应激反应中，但细胞骨架蛋白在DNA修复中的功能作用仍未被探索。在这里，我们发现dna损伤剂诱导结直肠癌（CRC）细胞中平滑肌特异性细胞骨架蛋白平滑蛋白（SMTN）的大幅上调。沉默SMTN消除了G2/M阻滞，加重了DNA损伤，并显著增强了CRC细胞对各种DNA损伤剂的化学敏感性。值得注意的是，SMTN可以在激光照射后1分钟内快速积累在DNA损伤位点，这对于启动同源重组（homologous recombination， HR）修复是必不可少的。在机制上，SMTN通过破坏其与E3泛素连接酶HUWE1的相互作用来稳定RAD51，从而维持HR修复过程。为了探索SMTN的治疗作用，我们构建了定制的细胞膜注入仿生脂质体，以确保SMTN siRNA特异性快速递送到HCT-116细胞中，在体外和体内均显著增强了伊立替康和呋唑帕利的抗癌作用。总之，我们的研究结果揭示了SMTN在DNA损伤修复中的新功能，并提供了一种靶向SMTN的治疗策略，以提高DNA损伤剂的疗效。

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引用次数: 0

Key imidazolyl groups that induce phenylalanine flipping enhance the efficacy of oral BRD9 inhibitors for AML treatment 诱导苯丙氨酸翻转的关键咪唑基团增强了口服BRD9抑制剂治疗AML的疗效

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 Epub Date: 2025-08-13 DOI: 10.1016/j.apsb.2025.08.006

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

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.

含溴结构域蛋白9 （BRD9）是哺乳动物SWI/SNF染色质重塑复合体ncBAF的核心亚基。BRD9已成为抗癌药物的潜在靶点，特别是在急性髓性白血病（AML）的治疗中。在这里，我们报道了10m （Y22073）和10t作为新的BRD9选择性溴域抑制剂。晶体学研究显示，从构效关系（SAR）中发现的关键活性咪唑基可以诱导Phe163翻转并显著增强化合物的细胞效力，使10m成为首个具有显著抗AML细胞活性的BRD9选择性抑制剂。我们还通过修饰现有的BRD9抑制剂验证了咪唑基的关键作用。代表性化合物10m和10t对BRD9溴域具有较强的结合亲和力和选择性，能显著抑制AML细胞系的增殖。10m也表现出良好的代谢稳定性、溶解度和药代动力学特性。此外，口服化合物10m和10t在MV4-11异种移植小鼠模型中显示出强大的抗肿瘤功效。有效的、选择性的、可口服的BRD9溴域抑制剂可能解决BRD9抑制剂所面临的细胞活性弱和表型功效有限的挑战，并作为开发用于治疗AML的抗癌药物的新先导化合物。

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引用次数: 0

Undulanoids A−D: Unexpected sesterterpenoids as potent S100A8/A9 complex inhibitors for psoriasis treatment 波曲酸A - D：意外的酯萜类化合物作为有效的S100A8/A9复合物抑制剂治疗牛皮癣

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 Epub Date: 2025-09-11 DOI: 10.1016/j.apsb.2025.09.006

Yuyi Zheng , Xiaotian Zhang , Xiaoxia Gu , Yongqi Li , Qin Li , Yingli Zhu , Bingbing Dai , Yu Liang , Ruping Fan , Chunmei Chen , Weiguang Sun , Yonghui Zhang , Hucheng Zhu

Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques, and remains a challenge in its management. Blocking the release or inflammatory effects of two proinflammatory molecules of the S100-alarmin family, S100A8 and S100A9, in keratinocytes is a promising strategy for future therapeutic approaches. Undulanoids A−D (1−4), four novel sesterterpenoids possessing a highly congested pentacyclic 6/5/5/6/5 ring system with eight stereogenic centers, including three all-carbon quaternary centers, two quaternary carbon centers at the bridgehead, and a 1,4,11-trimethyltricyclo[5.3.1.0^4,11]undecane fragment, were isolated from Aspergillus undulatus. Their structures were elucidated by spectroscopic data and single-crystal X-ray diffraction. Strikingly, undulanoid B (2), the most promising lead compound, inhibits the expression of genes related to tumor necrosis factor and interleukin-17 signaling pathways. Furthermore, reverse target prediction, cellular thermal shift assay, and dynamic simulation indicated that compound 2 could target with the expression of S100A9 and keratinocyte proliferation. As the pioneering S100A8/A9 complex and inhibit its secretion. Moreover, compound 2 showed a potent therapeutic effect on the psoriasiform skin lesions induced by imiquimod in mice by inhibiting the expression of S100A9 and keratinocyte proliferation. As the pioneering examples of natural products demonstrate inhibitory action against S100A8/A9 complex, this discovery provides a series of compelling lead compounds with novel molecular scaffold for treating psoriasis.

牛皮癣是一种常见的免疫介导的皮肤疾病，表现为异常的皮肤斑块，并且在其管理方面仍然是一个挑战。阻断s100 -报警蛋白家族的两种促炎分子S100A8和S100A9在角化细胞中的释放或炎症作用是未来治疗方法的一个有希望的策略。从波曲霉（Aspergillus）中分离到四种新型甾萜类化合物Undulanoids A−D(1−4)，它们具有高度密集的6/5/5/6/5五环体系，具有8个立体中心，包括3个全碳季中心、桥头堡的2个季碳中心和一个1,4,11-三甲基三环[5.3.1.04,11]十一烷片段。通过光谱数据和单晶x射线衍射对其结构进行了表征。引人注目的是，最有希望的先导化合物波曲样B(2)抑制肿瘤坏死因子和白细胞介素-17信号通路相关基因的表达。此外，反向靶标预测、细胞热移实验和动态模拟表明，化合物2可以靶向S100A9的表达和角化细胞的增殖。首创S100A8/A9复合物，抑制其分泌。此外，化合物2通过抑制S100A9的表达和角化细胞的增殖，对咪喹莫特诱导的小鼠银屑病样皮损有明显的治疗作用。作为天然产物对S100A8/A9复合物具有抑制作用的先驱，这一发现为治疗银屑病提供了一系列具有新颖分子支架的先导化合物。

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引用次数: 0

LSD1 inhibition sensitizes anti-PD1 blockade immunotherapy by inhibiting the long-range attack of tumor-derived extracellular vesicles LSD1抑制通过抑制肿瘤源性细胞外囊泡的远程攻击使抗pd1阻断免疫治疗增敏

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 Epub Date: 2025-10-28 DOI: 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.

程序性细胞死亡蛋白-1/程序性细胞死亡配体-1 （PD1/PD-L1）阻断剂在癌症治疗中显示出希望，但仍然受到低反应率的限制。最近的努力探索了提高免疫治疗疗效的策略。抑制组蛋白赖氨酸特异性去甲基化酶1 （LSD1）可通过下调PD-L1表达增强肿瘤免疫应答。此外，肿瘤细胞源性细胞外囊泡（EVs）中的PD-L1有助于免疫抑制肿瘤微环境（TME）并促进免疫逃避。本研究发现LSD1抑制可介导PD-L1在肿瘤细胞表面的重排，降低ev的分泌和TME中PD-L1的水平，最终阻断肿瘤细胞释放ev引起的远程免疫抑制。因此，我们开发了一种针对tme的协同治疗系统，该系统具有双重机制，抗pd1治疗阻断免疫检查点，连翘苷a （FA）作为LSD1抑制剂调节ev分泌。CD4+ T细胞通过诱导G1/S细胞周期阻滞直接杀伤肿瘤细胞。最终，该系统激活TME内的肿瘤免疫应答，有效抑制非小细胞肺癌肿瘤的生长。我们的工作强调了ev的信号作用和CD4+ T细胞阻止细胞周期的能力，为增强抗pd1 /PD-L1治疗的应答提供了一种新的方法。

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引用次数: 0

Rational engineering of degradation tail-driven CELMoD–antibody conjugates for precision malignancy therapy 用于恶性肿瘤精确治疗的降解尾驱动的celmod抗体偶联物的合理工程设计

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 Epub Date: 2025-09-12 DOI: 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.

降解抗体偶联物（降解抗体偶联物，dac）是一种很有前途的针对血液恶性肿瘤的药物模式，但仍然缺乏合理的设计框架。在这里，我们通过系统的探索，展示了合理的抗体-降解物相容性和降解尾衍生共轭性的策略。受IKZF1/3降解物成功的启发，我们试图探索小脑E3连接酶调节剂（celmod）在构建新型偶联物方面的潜力。通过将模块化文库与新底物筛选和进一步的共轭衍生相结合，确定了I034，这是一种具有皮摩尔降解活性和抗增殖作用的有效CELMoD有效载荷。通过连接物化学，构建了基于i034的DACs，在体外和体内均显示出比基于auristatin的偶联物更优越的疗效和安全性，靶向cd38的Dara-VA-I034在低剂量下实现了完全的肿瘤根除。机制揭示了CD38偶联物明显的正反馈调节，强调了有效载荷和抗原之间兼容性的需要。这些结果表明，该方法可以为发现CELMoD有效载荷和推进dac治疗多发性骨髓瘤和其他恶性肿瘤提供一个框架。

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引用次数: 0

Decoding helical dynamics in viral replication: Cryo-EM unveils conserved assembly mechanisms and broad-spectrum antiviral targets 解码病毒复制中的螺旋动力学：Cryo-EM揭示了保守的组装机制和广谱抗病毒靶点

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 Epub Date: 2025-08-30 DOI: 10.1016/j.apsb.2025.08.026

Bo Wang, Jiwei Zhang, Xinyong Liu, Peng Zhan

引用次数: 0

ROS-scavenging nanomaterials as emerging tools for bone tissue regeneration: A comprehensive review of recent progress 清除活性氧纳米材料作为骨组织再生的新兴工具：近期进展的全面回顾

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 Epub Date: 2025-09-27 DOI: 10.1016/j.apsb.2025.09.040

Wanzhuo He , Tian Xu , Miao Wang , Ni Ni , Yun Su , Xianqun Fan

Bone defects, characterized by a loss of skeletal structure integrity, represent a prevalent clinical challenge affecting millions of patients. While bone autografts and allografts offer potential solutions, limitations, including donor scarcity, immune rejection, anatomical constraints, and complications arising from host comorbidities such as diabetes, often lead to unsatisfactory outcomes. This necessitates the need for alternative treatments. Researchers have identified that reactive oxygen species (ROS) play a crucial role in bone regeneration. Although physiological ROS levels are essential for normal healing, excessive ROS accumulation disrupts the balance between bone formation and resorption, hindering regeneration. Antioxidants can mitigate oxidative stress by scavenging ROS or inhibiting their formation, thereby restoring the equilibrium between bone formation and resorption. Advances in nanotechnology have enabled the development of various ROS-scavenging nanomaterials with enhanced therapeutic efficacy. These nanomaterials either function as delivery platforms for conventional antioxidants or as direct ROS-neutralizing agents through intrinsic redox or enzyme-mimicking properties. This review comprehensively summarizes ROS-scavenging nanomaterials for bone tissue regeneration, focusing on their design strategies, underlying mechanisms, applications, and potential for clinical translation.

骨缺损以骨骼结构完整性丧失为特征，是影响数百万患者的普遍临床挑战。虽然自体骨移植和同种异体骨移植提供了潜在的解决方案，但局限性，包括供体稀缺、免疫排斥、解剖限制以及由宿主合并症（如糖尿病）引起的并发症，往往导致不满意的结果。这就需要替代疗法。研究人员已经发现活性氧（ROS）在骨再生中起着至关重要的作用。虽然生理上的ROS水平对正常愈合至关重要，但过多的ROS积累会破坏骨形成和骨吸收之间的平衡，阻碍再生。抗氧化剂可以通过清除ROS或抑制其形成来减轻氧化应激，从而恢复骨形成和骨吸收之间的平衡。纳米技术的进步使各种清除活性氧的纳米材料得以发展，并增强了治疗效果。这些纳米材料既可以作为常规抗氧化剂的递送平台，也可以通过内在的氧化还原或酶模拟特性作为直接的ros中和剂。本文综述了用于骨组织再生的ros清除纳米材料，重点介绍了它们的设计策略、潜在机制、应用和临床转化潜力。

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