Journal of Controlled Release最新文献_第2页

Lipid nanoparticles containing zwitterionic lipids versatilely enhance the efficiency of mRNA delivery 含有两性离子脂质的脂质纳米颗粒可全面提高mRNA的递送效率

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-08 DOI: 10.1016/j.jconrel.2026.114709

Yuichi Suzuki , Yuma Yamada , Hideyoshi Harashima , Yusuke Sato

Ionizable lipids enable lipid nanoparticles (LNPs) to deliver nucleic acids, including mRNA, to target cells. However, the efficiency of the endosomal escape of conventional LNPs remains limited to a small percentage. Lipid components that actively interact with net-neutral phospholipids in endosomal membranes and promote membrane fusion potentially enhance the efficiency of endosomal escape and further improve functional mRNA delivery. In this study, we developed a zwitterionic tri-oleoyl-Tris (zTOT) library and used it to enhance mRNA delivery by replacing the widely used helper lipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) in LNPs with zTOT. LNPs containing TOT-15, an example of zTOT, demonstrated a 5-fold higher gene expression compared with that of DSPC-LNPs. TOT-15-LNPs composed of commercially available ionizable lipids showed enhanced gene expression compared with that of DSPC-LNPs. The TOT-15-LNPs also showed almost 100% gene knockout efficiency with no toxicity. The TOT-15 system interacts with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and induces a non-lamellar structure. Pharmacokinetic calculation revealed that endosomal escape efficiency of the TOT-15-LNPs was more than 9.6%. In summary, the results of this study demonstrate that the zTOT system enhances the efficiency of both endosomal escape and functional mRNA delivery.

可电离脂质使脂质纳米颗粒（LNPs）能够将核酸（包括mRNA）递送到靶细胞。然而，传统LNPs的内体逃逸效率仍然局限于很小的百分比。与内体膜中净中性磷脂积极相互作用并促进膜融合的脂质成分可能提高内体逃逸效率并进一步改善mRNA的功能性传递。在这项研究中，我们建立了一个两性离子三油酰三（zTOT）文库，并用zTOT取代LNPs中广泛使用的辅助脂质1,2-二硬脂酰- san -甘油-3-磷酸胆碱（dsc）来增强mRNA的传递。以zTOT为例，含有TOT-15的LNPs的基因表达量比含有DSPC-LNPs的LNPs高5倍。由市售可电离脂质组成的TOT-15-LNPs与DSPC-LNPs相比，基因表达增强。TOT-15-LNPs也显示出几乎100%的基因敲除效率，而且没有毒性。TOT-15体系与1-棕榈酰-2-油基- cn -甘油-3-磷酸胆碱（POPC）相互作用，诱导出非层状结构。药代动力学计算表明，TOT-15-LNPs的内体逃逸效率大于9.6%。总之，本研究的结果表明，zTOT系统提高了内体逃逸和功能性mRNA传递的效率。

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引用次数: 0

A comprehensive review on the storage stability of extracellular vesicles for clinical translation: Current status, challenges, and prospects 临床翻译用细胞外囊泡储存稳定性综述：现状、挑战和前景

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-08 DOI: 10.1016/j.jconrel.2026.114706

Hai Huang , Wenjie Xu , Xinyan Hao , Pengcheng Sun , Mengen Guo , Muyan Li , Xinying Liu , Yanjin Peng , Ruyue Han , Tiantian Tang , Yucheng Tang , Daxiong Xiang , Ming Wang , Junyong Wu

Extracellular vesicles (EVs) are now seen as powerful tools for next-generation diagnostics, targeted drug delivery, and cell-free therapies. Their clinical application, however, is constrained by storage challenges—the preservation process compromises their structure and activity. This review summarizes current methods for preserving EVs, including cryopreservation, spray-drying, and freeze-drying. It also discusses how suboptimal storage conditions affect the critical quality attributes (CQAs) of EVs, including membrane integrity, cargo stability, biological activity, immunogenicity, and recovery efficiency. This review adopts an application-oriented approach, highlighting the distinct stability requirements for EVs serving as diagnostic markers, delivery vehicles, or therapeutic agents. Furthermore, it also evaluated new optimization strategies, such as a reasonable cryopreservation protective agent formulation, an improved buffer solution formulation, reduced adsorption storage materials, and advanced material-based stable technologies. Finally, this review outlines the future directions, emphasizing the need to adopt standardized and scalable preservation methods that are oriented towards EV clinical applications, to accelerate the transition of EV-based technologies from the laboratory to clinical practice.

细胞外囊泡（EVs）现在被视为下一代诊断、靶向药物递送和无细胞治疗的强大工具。然而，它们的临床应用受到储存挑战的限制——保存过程损害了它们的结构和活性。本文综述了目前保存ev的方法，包括低温保存、喷雾干燥和冷冻干燥。本文还讨论了次优储存条件如何影响电动汽车的关键质量属性（cqa），包括膜完整性、货物稳定性、生物活性、免疫原性和回收效率。本综述采用应用为导向的方法，强调了电动汽车作为诊断标志物、运载工具或治疗剂的独特稳定性要求。此外，还评估了新的优化策略，如合理的冷冻保护剂配方、改进的缓冲溶液配方、减少吸附储存材料和先进的材料基稳定技术。最后，本文概述了未来的发展方向，强调需要采用面向EV临床应用的标准化和可扩展的保存方法，以加速EV技术从实验室向临床实践的过渡。

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引用次数: 0

Wound healing under the regulation of mechanically active biomaterials: From mechanism exploration to scar prevention 机械活性生物材料调控下的创面愈合：从机制探索到疤痕预防

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-07 DOI: 10.1016/j.jconrel.2026.114700

Huiqi Zhang , Dong Luo , Guojun Cai , Manman Hu , Zhen Fan , Meng Li

Severe cutaneous injury predictably culminates in scar formation, typified by the loss of skin appendages and a consequent impairment of both structural integrity and physiological function. A growing body of evidence now indicates that mechanical cues are as determinative as biochemical signals in directing cutaneous repair and scar formation. Accordingly, mechanomodulatory biomaterials have emerged as promising platforms for promoting scar-free wound repair. However, the mechanistic bases by which mechanical forces remodel the extracellular milieu—and how such forces can be rationally exploited to reprogram mechanotransductive signaling—remain incompletely resolved. This knowledge gap poses a major barrier to the clinical translation of mechanotherapeutic approaches. In this review, we synthesize current understanding of cutaneous biomechanics and its intimate interplay with wound-healing cascades, and we delineate the principal mechanotransduction pathways that convert physical stimuli into cellular fate decisions. We further provide a critical appraisal of recent advances in mechanically active dressings designed to deliver spatially and temporally controlled mechanical cues that bias tissue repair toward regeneration. Finally, we identify outstanding challenges and propose future directions for the development of mechanoregulated biomaterials, offering a strategic roadmap to accelerate the translation of scarless healing strategies into clinical practice.

严重的皮肤损伤可预见地最终形成疤痕，典型的特征是皮肤附属物的丧失和随之而来的结构完整性和生理功能的损害。越来越多的证据表明，在指导皮肤修复和疤痕形成方面，机械信号与生化信号一样具有决定性。因此，机械调节生物材料已成为促进无疤痕伤口修复的有前途的平台。然而，机械力重塑细胞外环境的机制基础，以及如何合理利用这些力来重新编程机械转导信号，仍然没有完全解决。这种知识差距是机械治疗方法临床转化的主要障碍。在这篇综述中，我们综合了目前对皮肤生物力学的理解及其与伤口愈合级联反应的密切相互作用，并描述了将物理刺激转化为细胞命运决定的主要机械转导途径。我们进一步对机械活性敷料的最新进展进行了批判性评估，这些敷料旨在提供空间和时间控制的机械线索，使组织修复偏向再生。最后，我们确定了突出的挑战，并提出了机械调节生物材料发展的未来方向，为加速将无疤痕愈合策略转化为临床实践提供了战略路线图。

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引用次数: 0

Intrapericardial delivery of FAP-CAR-T cells via a ROS-responsive hydrogel to treat cardiac fibrosis 经ros反应水凝胶心包内递送FAP-CAR-T细胞治疗心脏纤维化

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-07 DOI: 10.1016/j.jconrel.2026.114697

Bihui Cao , Manting Liu , Sainiwaer Anwaier , Xiang Long , Ting You , Zijian He , Haotao Su , Xinkui Zhang , Jiaqi Wang , Huanlei Huang , Nanbo Liu , Yujie Jiang , Hongmo Xiang , Yehuda G. Assaraf , Xiaolan Zhu , Xuelei Ma , Qi Zhao , Ping Zhu , Lu Wang

Cardiac fibrosis is a key pathological feature of both acute and chronic heart diseases, characterized by abnormal accumulation of extracellular matrix resulting from fibroblast activation. Although fibroblast activation protein (FAP)-targeted chimeric antigen receptor (CAR) T cell therapy has shown promise in selectively eliminating activated fibroblasts, systemic administration remains limited by off-target toxicity and insufficient trafficking to the diseased myocardium. Here, we present a reactive oxygen species (ROS)-responsive hydrogel designed for intrapericardial delivery of FAP-specific CAR-T (FAP-CAR-T) cells to locally treat post-myocardial infarction (MI) fibrosis. This hydrogel, based on a thioketal-crosslinked polyethylene glycol matrix, selectively degrades in the ROS-enriched microenvironment of fibrotic tissue, enabling the controlled release of encapsulated FAP-CAR-T cells. In vitro, FAP-CAR-T cells exhibited antigen-dependent cytotoxicity against FAP⁺ targets, and hydrogel-encapsulated CAR-T cells maintained robust proliferation and showed ROS-triggered release kinetics. Using murine models of MI-induced fibrosis, the hydrogel-based intrapericardial delivery strategy enhanced FAP-CAR-T cells infiltration, persistence, and effector function, resulting in significant depletion of activated fibroblasts, attenuation of fibrotic remodeling, and preservation of cardiac structure and left ventricular function. This hydrogel-based CAR-T immunotherapeutic platform provides a localized, targeted, and on-demand strategy for combating cardiac fibrosis and may offer broader translational potential for the treatment of fibrotic diseases.

心脏纤维化是急性和慢性心脏病的一个关键病理特征，其特征是由成纤维细胞激活引起的细胞外基质的异常积累。尽管以成纤维细胞活化蛋白（FAP）为靶点的嵌合抗原受体（CAR） T细胞疗法在选择性消除活化的成纤维细胞方面显示出了希望，但系统给药仍然受到脱靶毒性和病变心肌运输不足的限制。在这里，我们提出了一种活性氧（ROS）反应的水凝胶，设计用于心包内递送fap特异性CAR-T （FAP-CAR-T）细胞来局部治疗心肌梗死后（MI）纤维化。这种水凝胶基于硫酮交联聚乙二醇基质，在富含ros的纤维化组织微环境中选择性降解，使被封装的FAP-CAR-T细胞得以控制释放。在体外，FAP-CAR-T细胞对FAP+靶点表现出抗原依赖性的细胞毒性，水凝胶包裹的CAR-T细胞保持强劲的增殖，并表现出ros触发的释放动力学。在mi诱导的小鼠纤维化模型中，基于水凝胶的心包内递送策略增强了FAP-CAR-T细胞的浸润、持久性和效应功能，导致活化成纤维细胞的显著耗竭，纤维化重塑的衰减，心脏结构和左心室功能的保存。这种基于水凝胶的CAR-T免疫治疗平台为对抗心脏纤维化提供了一种局部、靶向和按需的策略，并可能为纤维化疾病的治疗提供更广泛的转化潜力。

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引用次数: 0

Molecular engineering of designer diabetes therapeutics 设计糖尿病治疗的分子工程

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-07 DOI: 10.1016/j.jconrel.2026.114705

Emily L. DeWolf, Bernice Webber, Matthew J. Webber

Biologic therapies for diabetes have advanced significantly through molecular engineering strategies that optimize therapeutic stability, pharmacokinetics, and delivery. This review presents an integrated overview of design principles used to develop insulin, glucagon, amylin analogs, and GLP-1 receptor agonists, highlighting their unique physicochemical challenges and therapeutic requirements. Structural modifications—including amino acid substitutions, peptide stapling, glycosylation, and PEGylation—are discussed for their roles in enhancing stability, reducing aggregation, and extending half-life. Strategies for tuning pharmacokinetics are examined, ranging from sequence-driven solubility modulation to formulation-based depot formation and vascular binding mechanisms. Various administration routes, including oral, inhaled, and intranasal delivery, are evaluated for their potential to improve adherence and more closely mimic endogenous hormone profiles. The review also addresses the development of combination therapies and multi-receptor agonists designed to synergize complementary hormonal pathways. Finally, recent progress in glucose-responsive systems is reviewed, emphasizing molecular and materials-based approaches that enable real-time, glucose-triggered therapeutic activation. Taken together, the evolution of diabetes therapeutics exemplifies the application of core molecular design concepts in biologic drug development. The strategies outlined herein not only address the complex demands of glycemic control but also provide a broadly applicable framework for engineering next-generation protein-based therapies for applications beyond diabetes.

通过优化治疗稳定性、药代动力学和递送的分子工程策略，糖尿病的生物治疗取得了显著进展。本文综述了用于开发胰岛素、胰高血糖素、胰淀素类似物和GLP-1受体激动剂的设计原则，强调了它们独特的物理化学挑战和治疗要求。结构修饰——包括氨基酸取代、肽钉接、糖基化和聚乙二醇化——讨论了它们在增强稳定性、减少聚集和延长半衰期方面的作用。调整药代动力学的策略被检查，范围从序列驱动的溶解度调节到基于配方的仓库形成和血管结合机制。各种给药途径，包括口服、吸入和鼻内给药，评估其改善依从性和更接近内源性激素谱的潜力。该综述还讨论了联合疗法和多受体激动剂的发展，旨在协同补充激素途径。最后，回顾了葡萄糖反应系统的最新进展，强调了基于分子和材料的方法，使实时葡萄糖触发的治疗激活成为可能。综上所述，糖尿病治疗方法的发展体现了核心分子设计概念在生物药物开发中的应用。本文概述的策略不仅解决了血糖控制的复杂需求，而且为设计下一代基于蛋白质的治疗方法提供了一个广泛适用的框架，用于糖尿病以外的应用。

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引用次数: 0

Engineering red blood cells for antigen-specific immune tolerance and personalized therapy of autoimmune diseases 工程红细胞抗原特异性免疫耐受和自身免疫性疾病的个性化治疗

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-07 DOI: 10.1016/j.jconrel.2026.114681

Yeshuang Yuan , Mengfan Yu , Xingxing Zhu , Wei Sun , Jing Li , Yiming Wang , Shanbo Yang , Yingying Shi , Zhaolin Wang , Xinyue Wang , Fudi Wang , Yue Xu , Min Wang , Jin Hu , Bo Zhang , Yudong Liu , Xuan Zhang

Current therapies for autoimmune diseases largely rely on broad-spectrum immunosuppressants and biologics, which indiscriminately deplete T or B cells. These approaches are largely constrained by systemic immunosuppression and off-target toxicities. Achieving durable, antigen-specific immune tolerance while preserving protective immunity against pathogens remains a long-standing goal in clinical practice. Here, we present a modular red blood cell (RBC)-based platform that induces antigen-specific tolerance through strain-promoted azide-alkyne cycloaddition (SPAAC)-mediated surface conjugation of disease-relevant peptides. We demonstrated that RBCs engineered by such approach retain their biophysical integrity and biocompatibility across a broad range of conjugation concentrations in vitro. Critically, when conjugated with single or multiple autoantigenic epitopes, these engineered RBCs elicited robust antigen-specific tolerance and drove durable disease remission in two well-established preclinical models, experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). Further mechanistic investigations revealed that the engineered RBCs reprogram antigen-presenting cells (APCs) toward a tolerogenic phenotype. This reprogramming, in turn, induces anergy in autoreactive T cells and suppresses the activation of autoreactive B cells. Collectively, this work establishes a versatile and clinically translatable platform, offering a path toward personalized, antigen-specific therapy for autoimmune diseases.

目前自身免疫性疾病的治疗主要依赖于广谱免疫抑制剂和生物制剂，这些药物会不加选择地消耗T细胞或B细胞。这些方法在很大程度上受到全身免疫抑制和脱靶毒性的限制。在保持对病原体的保护性免疫的同时，实现持久的抗原特异性免疫耐受仍然是临床实践中的长期目标。在这里，我们提出了一个基于红细胞（RBC）的模块化平台，该平台通过菌株促进叠氮-炔环加成（SPAAC）介导的疾病相关肽的表面偶联诱导抗原特异性耐受性。我们证明，通过这种方法设计的红细胞在体外广泛的偶联浓度范围内保持其生物物理完整性和生物相容性。关键的是，当与单个或多个自身抗原表位结合时，这些工程红细胞在两种成熟的临床前模型，实验性自身免疫性脑脊髓炎（EAE）和胶原诱导关节炎（CIA）中引发了强大的抗原特异性耐受性，并推动了持久的疾病缓解。进一步的机制研究表明，工程红细胞将抗原呈递细胞（APCs）重新编程为耐受性表型。这种重编程反过来诱导自身反应性T细胞的能量，并抑制自身反应性B细胞的激活。总的来说，这项工作建立了一个通用的、临床可翻译的平台，为自身免疫性疾病的个性化、抗原特异性治疗提供了一条途径。

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引用次数: 0

A versatile self-adjuvanting macro-microporous ZIF-8@Mn MOF platform for efficient antigen capture and presentation to boost antitumor immunity 一个多功能的自调节宏微孔ZIF-8@Mn MOF平台，用于有效的抗原捕获和呈递，以增强抗肿瘤免疫

IF 10.8 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-07 DOI: 10.1016/j.jconrel.2026.114707

Qinhua Zuo, Linghong Huang, Yanping Wang, Yifan Cai, Yahui Chen, Chuanxu Zhu, Zonghua Liu, Kewei Wang, Wei Xue

Personalized in situ tumor vaccines (ISTVs) have emerged as a promising approach to activating potent T cell-mediated anticancer immunity through the induction of immunogenic cell death (ICD) and the subsequent release of tumor-associated antigens (TAAs). However, their efficacy is limited by non-specific ICD, inadequate TAAs cross-presentation, and the stubborn immunosuppressive tumor microenvironment (TME). Here, we develop a novel ISTV platform (SOM-ZIF-8@Mn/ARV) integrating a specific ICD inducer (ARV-825), and a multifunctional antigen catcher (SOM-ZIF-8@Mn) to boost antitumor immunity. ARV-825, as a protein targeted degradation chimera (PROTAC), selectively degrades bromodomain-containing protein4 (BRD4) to induce potent ICD, while the produced TAAs are effectively captured by SOM-ZIF-8@Mn to in situ generate a vaccination effect. Leveraging its unique hierarchical porous structure and rough surface, SOM-ZIF-8@Mn exhibits enhanced antigen capture efficiency, enabling the adsorption of both soluble TAAs and tumor cell fragments. Additionally, Mn²⁺ released from SOM-ZIF-8@Mn under TME conditions activates the STING pathway, promotes dendritic cell maturation and antigen cross-presentation, thereby activating CD8⁺ T cells for efficient tumor-specific immunity. Furthermore, the platform reprograms tumor-associated macrophages into pro-inflammatory M1 phenotypes, alleviating TME immunosuppression. This ISTV platform triggers robust antitumor immunity and achieves significant tumor growth inhibition when combined with αPD-1 blockade. The SOM-ZIF-8@Mn/ARV platform represents a powerful and effective advancement in improving the antitumor immune efficiency of ISTVs, offering a straightforward approach to the challenges faced in tumor immunotherapy.

通过诱导免疫原性细胞死亡（ICD）和随后释放肿瘤相关抗原（TAAs），个性化原位肿瘤疫苗（istv）已成为一种有希望激活T细胞介导的强效抗癌免疫的方法。然而，它们的疗效受到非特异性ICD、taa交叉呈递不足和顽固的免疫抑制肿瘤微环境（TME）的限制。在这里，我们开发了一种新的ISTV平台（SOM-ZIF-8@Mn/ARV），整合了特异性ICD诱导剂（ARV-825）和多功能抗原捕集器（SOM-ZIF-8@Mn）来增强抗肿瘤免疫。ARV-825作为蛋白靶向降解嵌合体（PROTAC），选择性降解含溴结构域蛋白4 （BRD4）诱导强效ICD，而产生的taa被SOM-ZIF-8@Mn有效捕获以原位产生疫苗接种效果。利用其独特的分层多孔结构和粗糙的表面，SOM-ZIF-8@Mn具有增强的抗原捕获效率，能够吸附可溶性TAAs和肿瘤细胞片段。此外，在TME条件下，SOM-ZIF-8@Mn释放的Mn2+激活STING通路，促进树突状细胞成熟和抗原交叉递呈，从而激活CD8+ T细胞，实现高效的肿瘤特异性免疫。此外，该平台将肿瘤相关巨噬细胞重编程为促炎性M1表型，减轻TME免疫抑制。该ISTV平台可触发强大的抗肿瘤免疫，并与αPD-1阻断剂联合使用可显著抑制肿瘤生长。SOM-ZIF-8@Mn/ARV平台在提高istv抗肿瘤免疫效率方面取得了强大而有效的进展，为肿瘤免疫治疗面临的挑战提供了一种直接的方法。

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引用次数: 0

Injectable hydrogel induces tumor cell extracellular calcification and bone regeneration to disrupt the osteolytic vicious cycle in bone metastasis 可注射水凝胶诱导肿瘤细胞细胞外钙化和骨再生，破坏骨转移过程中溶骨的恶性循环

IF 10.8 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-07 DOI: 10.1016/j.jconrel.2026.114701

Minzhao Lin, Shaohui Deng, Simin Liang, Yujie Jiang, Qi Chen, Gengjia Chen, Bo Li, Yujun Cai, Xiaoxue Xie, Xintao Shuai, Zecong Xiao

Bone metastasis is a significant challenge in the treatment of advanced breast cancer, with current treatments mainly providing symptom relief without addressing the osteolytic cycle driven by tumor cells and osteoclasts, which leads to continuous bone destruction and tumor progression. Pamidronate (APD), a nitrogen-containing bisphosphonate, has shown potential in managing osteolytic lesions by inhibiting osteoclast activity. However, its clinical application is hindered by rapid systemic clearance and off-target effects. Herein, we developed a multifunctional injectable hydrogel (CHA) by covalently conjugating APD to enhance localized delivery, reduce toxicity, and target both tumor progression and bone degradation to disrupt osteolytic cycle. The CHA hydrogel induces membrane calcification in tumor cells, forming a mineralized layer that impairs nutrient exchange and suppresses tumor growth. Concurrently, CHA modulates the bone microenvironment by downregulating PTHrP expression, inhibiting osteoclastogenesis, and promoting osteogenesis through the upregulation of OPG and RUNX2. Both in vitro and in vivo experiments demonstrated that CHA significantly inhibited tumor growth, prevented bone loss, and facilitated bone regeneration. Moreover, CHA exhibited excellent biocompatibility with no observed systemic toxicity. These results underscore the promise of CHA as a clinically translatable therapeutic strategy for the treatment of osteolytic bone metastases.

骨转移是晚期乳腺癌治疗中的一个重大挑战，目前的治疗主要是提供症状缓解，而没有解决由肿瘤细胞和破骨细胞驱动的溶骨周期，导致持续的骨破坏和肿瘤进展。帕米膦酸盐（APD）是一种含氮的双膦酸盐，已显示出通过抑制破骨细胞活性来管理溶骨病变的潜力。然而，它的临床应用受到全身快速清除和脱靶效应的阻碍。在此，我们开发了一种多功能注射水凝胶（CHA），通过共价偶联APD来增强局部递送，降低毒性，并针对肿瘤进展和骨降解来破坏溶骨周期。CHA水凝胶诱导肿瘤细胞膜钙化，形成矿化层，损害营养物质交换，抑制肿瘤生长。同时，CHA通过下调PTHrP表达，抑制破骨细胞生成，通过上调OPG和RUNX2促进骨生成，从而调节骨微环境。体外和体内实验均表明，CHA能显著抑制肿瘤生长，防止骨质流失，促进骨再生。此外，CHA具有良好的生物相容性，没有观察到全身毒性。这些结果强调了CHA作为治疗溶骨性骨转移的临床可翻译治疗策略的前景。

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引用次数: 0

Smart gel tectonics: 3D-printed starch-chitosan architectures with pH-responsive magnesium delivery for targeted intestinal repletion 智能凝胶构造：3d打印淀粉-壳聚糖结构与ph响应镁递送靶向肠道充值

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-07 DOI: 10.1016/j.jconrel.2026.114702

Qiyong Guo, Weihang Cao, Ling Chen

The development of effective oral magnesium supplements is hindered by two major delivery challenges: rapid gastric leakage leading to gastrointestinal side effects, and non-targeted intestinal release resulting in poor absorption and compensatory excretion. To address this, we engineered an intelligent, intestinal-targeted delivery system based on pH-responsive oxidized maize starch (OMS)–chitosan (CS) composite hydrogels, fabricated via hot-extrusion microwave 3D printing (HEM-3DP). The system exhibited a unique gastric-phase structural adaptation: acidic conditions trigger CS dissolution and OMS carboxyl protonation, initiating a dynamic “ionic handoff” where Mg²⁺ was recaptured by exposed CS amines via coordination bonds. This mechanism reduced gastric Mg²⁺ release by >40% compared to CS-free controls, enabling precise spatiotemporal control with sustained small intestinal release (66.6–74.0%) and enhanced colon-targeted delivery (33.6–56.0% retention). Release kinetics were finely tuned by engineering OMS carboxyl content (0.36–1.57%) and molecular weight (6.84 × 10⁵–2.39 × 10⁶ Da), demonstrating programmable design. In magnesium-deficient mice, the optimized OMS2-CS-Mg²⁺ gel not only restored serum magnesium to physiological levels (1.35 ± 0.04 mmol/L) but also upregulated key intestinal (claudin1) and colonic (TRPM6/7) absorption transporters—a dual-pathway activation unattained by conventional MgCl₂ supplementation. This work elucidated a clear structure–mechanism–performance relationship governing nutrient release and absorption. It provided a robust, food-grade platform that integrated advanced manufacturing with material intelligence to achieve site-specific, controlled mineral delivery, offering a translatable strategy for oral supplementation and broadening the design principles for smart, responsive hydrogel-based delivery systems.

有效口服镁补充剂的开发受到两大递送挑战的阻碍：快速胃漏导致胃肠道副作用，非靶向肠道释放导致吸收和代偿排泄不良。为了解决这个问题，我们设计了一种基于ph响应氧化玉米淀粉(OMS) -壳聚糖（CS）复合水凝胶的智能肠道靶向递送系统，该系统通过热挤压微波3D打印（HEM-3DP）制造。该体系表现出独特的胃相结构适应性：酸性条件触发CS溶解和OMS羧基质子化，启动动态“离子切换”，其中Mg2+通过配位键被暴露的CS胺重新捕获。与不含cs的对照组相比，该机制使胃Mg2+释放减少了40%，实现了精确的时空控制，持续的小肠释放（66.6-74.0%）和增强的结肠靶向递送（33.6-56.0%保留率）。通过工程OMS羧基含量（0.36-1.57%）和分子量（6.84 × 105-2.39 × 106 Da）对释放动力学进行了精细调节，证明了可编程设计。在缺镁小鼠中，优化后的OMS2-CS-Mg2+凝胶不仅使血清镁恢复到生理水平（1.35 ± 0.04 mmol/L），而且还上调了关键的肠道（cldin1）和结肠（TRPM6/7）吸收转运蛋白，这是常规MgCl2补充剂无法达到的双途径激活。本研究阐明了营养物质释放和吸收的结构-机制-性能关系。它提供了一个强大的食品级平台，将先进制造与材料智能集成在一起，以实现特定地点的受控矿物输送，为口服补充提供了可翻译的策略，并拓宽了智能，响应性水凝胶输送系统的设计原则。

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引用次数: 0

Dual-payload small-molecule drug conjugates enable bystander anticancer activity with reduced nonspecific release 双载荷小分子药物偶联物可以通过减少非特异性释放来实现旁观者抗癌活性

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-06 DOI: 10.1016/j.jconrel.2026.114695

Chuanjie Chen , Yongzhang Pan , Na Zhang , Ting Yang , Jiaxin Shi , Bige Ren , Yonghan He , Xuan Zhang

Small-molecule drug conjugates (SMDCs) have emerged as a promising class of targeted therapeutics, yet their clinical translation has been hindered by suboptimal efficacy and safety, with conventional optimization largely restricted to variations in ligand design and linker chemistry. We propose a dual-payload strategy that enhances therapeutic efficacy while concurrently minimizing off-target diffusion that contributes to systemic toxicity. In this proof-of-concept study, a representative SMDC bearing two degrader payloads, termed Bi-LIVTAC (XZ1618), demonstrates improved targeted cytotoxicity and a robust bystander effect, accompanied by a significant reduction in receptor-independent uptake. Notably, XZ1618 achieves complete tumor regression in combination with sorafenib in a Huh-7 xenograft model, thereby markedly expanding the therapeutic window without inducing hematological toxicity or organ damage. Moreover, this dual-payload design is broadly applicable to SMDCs targeting other membrane receptors, such as folate receptor, and to diverse payload types, including conventional cytotoxins and fluorescent probes. These findings establish the dual-payload strategy as a versatile and translatable platform for developing next-generation SMDCs with improved therapeutic windows.

小分子药物偶联物（smdc）已经成为一种很有前途的靶向治疗药物，但它们的临床转化一直受到疗效和安全性不理想的阻碍，传统的优化主要局限于配体设计和连接体化学的变化。我们提出了一种双重有效载荷策略，可以提高治疗效果，同时最大限度地减少导致全身毒性的脱靶扩散。在这项概念验证研究中，一种具有代表性的SMDC携带两种降糖剂有效载荷，称为Bi-LIVTAC (XZ1618)，显示出改善的靶向细胞毒性和强大的旁观者效应，同时显著减少了与受体无关的摄取。值得注意的是，XZ1618与索拉非尼在Huh-7异种移植模型中实现了完全的肿瘤消退，从而显着扩大了治疗窗口，而不会引起血液学毒性或器官损伤。此外，这种双载荷设计广泛适用于靶向其他膜受体的smdc，如叶酸受体，以及不同的载荷类型，包括传统的细胞毒素和荧光探针。这些发现确立了双有效载荷策略作为开发具有改进治疗窗口的下一代smdc的通用和可翻译平台。

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