首页 > 最新文献

Journal of Controlled Release最新文献

英文 中文
Injectable acid-labile thermosensitive magnetic hydrogel with responsive drug release for bridging liver transplantation in hepatocellular carcinoma 可注射酸不稳定热敏磁水凝胶药物释放反应性用于肝癌桥接肝移植
IF 10.8 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2026-02-09 DOI: 10.1016/j.jconrel.2026.114685
Huai Yang, Jing-Long Hu, Yunjun Xu, Tian-Ci Sun, Xu Yan, Haojie Lu, Dongquan Liu, Baoqiang Cao, Yang Lu, Tao He
Percutaneous locoregional drug injection based on hydrogel therapy under image guidance is performed to limit the progression of hepatocellular carcinoma (HCC) and extend the waiting time for liver transplantation patients. However, achieving uniform distribution and sustained retention of drugs within the tumor bed remains a critical bottleneck urgently requiring breakthroughs in the current field of oncology. Here, an acid-labile thermosensitive hydrogel (denoted as NCD) with efficient magnetothermal functionality was developed by incorporating iron oxide nanoparticles (CION) and DOX into the ortho-ester-functionalized thermosensitive polymer matrix (poly(N-isopropylacrylamide270)-ortho ester-poly(ethylene glycol)). Engineered for multimodal therapy, the NCD hydrogel utilized an acid-cleavable backbone to achieve sustained DOX release (77.4 ± 2.1% at pH 6.5, 72 h), markedly exceeding the control release of 26.8 ± 2.7% and yielding uniform tumor drug distribution. Its thermosensitive PNIPAM matrix (LCST ≈ 32 °C) enabled injectable sol-gel transition at body temperature, allowing easy administration (maximum injection pressure: merely 6.0 ± 0.3 N) and forming a depot for prolonged drug retention. Combined with CION-enhanced magnetothermal therapy, ultrasound-guided NCD delivery suppressed orthotopic liver tumor growth, positioning it as a promising bridging strategy to transplantation.
以水凝胶治疗为基础,在图像引导下经皮局部注射药物,限制肝细胞癌(HCC)的进展,延长肝移植患者的等待时间。然而,实现药物在肿瘤床内的均匀分布和持续滞留仍然是当前肿瘤学领域迫切需要突破的关键瓶颈。本研究通过将氧化铁纳米颗粒(CION)和DOX加入到邻位酯功能化的热敏聚合物基体(聚n -异丙基丙烯酰胺270 -邻位酯-聚乙二醇)中,开发了一种具有高效磁热功能的酸不稳定热敏水凝胶(标记为NCD)。设计用于多模式治疗,NCD水凝胶利用酸可切割的骨架实现持续的DOX释放(77.4 ± 2.1%,pH 6.5,72 h),显着超过26.8 ± 2.7%的对照释放,并产生均匀的肿瘤药物分布。其热敏PNIPAM基质(LCST≈32 °C)在体温下实现可注射的溶胶-凝胶转变,允许易于给药(最大注射压力:仅6.0 ± 0.3 N)并形成长期药物保留库。结合离子增强磁热疗法,超声引导的NCD递送抑制原位肝肿瘤的生长,将其定位为一种有前途的桥接移植策略。
{"title":"Injectable acid-labile thermosensitive magnetic hydrogel with responsive drug release for bridging liver transplantation in hepatocellular carcinoma","authors":"Huai Yang, Jing-Long Hu, Yunjun Xu, Tian-Ci Sun, Xu Yan, Haojie Lu, Dongquan Liu, Baoqiang Cao, Yang Lu, Tao He","doi":"10.1016/j.jconrel.2026.114685","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114685","url":null,"abstract":"Percutaneous locoregional drug injection based on hydrogel therapy under image guidance is performed to limit the progression of hepatocellular carcinoma (HCC) and extend the waiting time for liver transplantation patients. However, achieving uniform distribution and sustained retention of drugs within the tumor bed remains a critical bottleneck urgently requiring breakthroughs in the current field of oncology. Here, an acid-labile thermosensitive hydrogel (denoted as NCD) with efficient magnetothermal functionality was developed by incorporating iron oxide nanoparticles (CION) and DOX into the ortho-ester-functionalized thermosensitive polymer matrix (poly(<ce:italic>N</ce:italic>-isopropylacrylamide<ce:inf loc=\"post\">270</ce:inf>)-ortho ester-poly(ethylene glycol)). Engineered for multimodal therapy, the NCD hydrogel utilized an acid-cleavable backbone to achieve sustained DOX release (77.4 ± 2.1% at pH 6.5, 72 h), markedly exceeding the control release of 26.8 ± 2.7% and yielding uniform tumor drug distribution. Its thermosensitive PNIPAM matrix (LCST ≈ 32 °C) enabled injectable sol-gel transition at body temperature, allowing easy administration (maximum injection pressure: merely 6.0 ± 0.3 N) and forming a depot for prolonged drug retention. Combined with CION-enhanced magnetothermal therapy, ultrasound-guided NCD delivery suppressed orthotopic liver tumor growth, positioning it as a promising bridging strategy to transplantation.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"89 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146631","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}
引用次数: 0
Single intravitreal injection of lipid nanoparticles delivering circular mRNA of nicotinamide phosphoribosyltransferase protects against dry AMD 单次玻璃体内注射脂质纳米颗粒,传递烟酰胺磷酸核糖基转移酶的环状mRNA,可预防干性AMD
IF 10.8 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2026-02-09 DOI: 10.1016/j.jconrel.2026.114691
Hui-Lin Li, Yu Xu, Jian-Shan Mo, Xin-Yuan Zhao, Cai-Ling Zhong, Zi-Wen Jia, Xiao-Long Wang, Ben-Chi Zhao, Yan-Ming Chen, Ke-Wei Zheng, Xiao-Lei Zhang, Qiao-Ping Wang
Age-related nicotinamide adenine dinucleotide (NAD+) deficiency is implicated in numerous pathologies, including dry age-related macular degeneration (AMD). Current NAD+-boosting strategies, reliant on precursors like nicotinamide mononucleotide (NMN), necessitate repeated dosing and offer transient effects, limiting therapeutic utility. Here, we address this critical limitation by developing a single-dose therapy using circular mRNA (circ-mRNA) to deliver functional nicotinamide phosphoribosyl transferase (NAMPT), the essential rate-limiting enzyme in NAD+ salvage. Engineered via permuted intron-exon (PIE) splicing, our circNAMPT exploits the exceptional stability and persistent translation capacity inherent to circular RNA scaffolds. Encapsulation in β-sitosterol-optimized lipid nanoparticles (LNPs) ensures robust intracellular delivery. In vitro, circNAMPT-LNP drives sustained NAMPT expression and prolonged NAD+ elevation, circumventing precursor limitations. In a stringent sodium iodate-induced dry AMD model, a single intravitreal circNAMPT-LNP injection matched the neuroprotective efficacy of 14 consecutive daily intraperitoneal NMN doses confirmed by histological integrity and functional preservation. This work establishes engineered circ-mRNAs as a transformative platform for durable, single-dose therapeutic protein delivery, demonstrates potential as a disease-modifying therapy for dry AMD. Its applicability extends broadly to systemic disorders driven by NAD+ deficiency in aging.
年龄相关性烟酰胺腺嘌呤二核苷酸(NAD+)缺乏与许多病理有关,包括干性年龄相关性黄斑变性(AMD)。目前的NAD+增强策略依赖于烟酰胺单核苷酸(NMN)等前体,需要重复给药并提供短暂效果,限制了治疗效用。在这里,我们通过开发一种使用环状mRNA (circ-mRNA)递送功能性烟酰胺磷酸核糖基转移酶(NAMPT)的单剂量治疗来解决这一关键限制,NAMPT是NAD+抢救中必不可少的限速酶。通过排列内含子-外显子(PIE)剪接,我们的cirnampt利用了环状RNA支架固有的卓越稳定性和持久翻译能力。包封在β-谷甾醇优化脂质纳米颗粒(LNPs)中,确保细胞内递送的稳定。在体外,cirnampt - lnp驱动持续的NAMPT表达和延长的NAD+升高,绕过前体限制。在严格的碘酸钠诱导的干性AMD模型中,单次玻璃体内注射cirnampt - lnp,其神经保护效果与连续14次每日腹腔注射NMN的神经保护效果相当,组织学完整性和功能保存得到了证实。这项工作建立了工程circ- mrna作为持久的,单剂量治疗性蛋白质递送的转化平台,证明了作为干性AMD的疾病改善疗法的潜力。它的适用性广泛扩展到由衰老中NAD+缺乏引起的全身性疾病。
{"title":"Single intravitreal injection of lipid nanoparticles delivering circular mRNA of nicotinamide phosphoribosyltransferase protects against dry AMD","authors":"Hui-Lin Li, Yu Xu, Jian-Shan Mo, Xin-Yuan Zhao, Cai-Ling Zhong, Zi-Wen Jia, Xiao-Long Wang, Ben-Chi Zhao, Yan-Ming Chen, Ke-Wei Zheng, Xiao-Lei Zhang, Qiao-Ping Wang","doi":"10.1016/j.jconrel.2026.114691","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114691","url":null,"abstract":"Age-related nicotinamide adenine dinucleotide (NAD<sup>+</sup>) deficiency is implicated in numerous pathologies, including dry age-related macular degeneration (AMD). Current NAD<sup>+</sup>-boosting strategies, reliant on precursors like nicotinamide mononucleotide (NMN), necessitate repeated dosing and offer transient effects, limiting therapeutic utility. Here, we address this critical limitation by developing a single-dose therapy using circular mRNA (circ-mRNA) to deliver functional nicotinamide phosphoribosyl transferase (NAMPT), the essential rate-limiting enzyme in NAD<sup>+</sup> salvage. Engineered via permuted intron-exon (PIE) splicing, our circNAMPT exploits the exceptional stability and persistent translation capacity inherent to circular RNA scaffolds. Encapsulation in β-sitosterol-optimized lipid nanoparticles (LNPs) ensures robust intracellular delivery. In vitro, circNAMPT-LNP drives sustained NAMPT expression and prolonged NAD<sup>+</sup> elevation, circumventing precursor limitations. In a stringent sodium iodate-induced dry AMD model, a single intravitreal circNAMPT-LNP injection matched the neuroprotective efficacy of 14 consecutive daily intraperitoneal NMN doses confirmed by histological integrity and functional preservation. This work establishes engineered circ-mRNAs as a transformative platform for durable, single-dose therapeutic protein delivery, demonstrates potential as a disease-modifying therapy for dry AMD. Its applicability extends broadly to systemic disorders driven by NAD<sup>+</sup> deficiency in aging.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"568 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146138283","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}
引用次数: 0
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 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。
{"title":"Lipid nanoparticles containing zwitterionic lipids versatilely enhance the efficiency of mRNA delivery","authors":"Yuichi Suzuki ,&nbsp;Yuma Yamada ,&nbsp;Hideyoshi Harashima ,&nbsp;Yusuke Sato","doi":"10.1016/j.jconrel.2026.114709","DOIUrl":"10.1016/j.jconrel.2026.114709","url":null,"abstract":"<div><div>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-<em>sn</em>-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-<em>sn</em>-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.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114709"},"PeriodicalIF":11.5,"publicationDate":"2026-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146644","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}
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 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。
{"title":"A comprehensive review on the storage stability of extracellular vesicles for clinical translation: Current status, challenges, and prospects","authors":"Hai Huang ,&nbsp;Wenjie Xu ,&nbsp;Xinyan Hao ,&nbsp;Pengcheng Sun ,&nbsp;Mengen Guo ,&nbsp;Muyan Li ,&nbsp;Xinying Liu ,&nbsp;Yanjin Peng ,&nbsp;Ruyue Han ,&nbsp;Tiantian Tang ,&nbsp;Yucheng Tang ,&nbsp;Daxiong Xiang ,&nbsp;Ming Wang ,&nbsp;Junyong Wu","doi":"10.1016/j.jconrel.2026.114706","DOIUrl":"10.1016/j.jconrel.2026.114706","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114706"},"PeriodicalIF":11.5,"publicationDate":"2026-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134050","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}
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 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。
{"title":"Wound healing under the regulation of mechanically active biomaterials: From mechanism exploration to scar prevention","authors":"Huiqi Zhang ,&nbsp;Dong Luo ,&nbsp;Guojun Cai ,&nbsp;Manman Hu ,&nbsp;Zhen Fan ,&nbsp;Meng Li","doi":"10.1016/j.jconrel.2026.114700","DOIUrl":"10.1016/j.jconrel.2026.114700","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114700"},"PeriodicalIF":11.5,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134058","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}
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 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。
{"title":"Intrapericardial delivery of FAP-CAR-T cells via a ROS-responsive hydrogel to treat cardiac fibrosis","authors":"Bihui Cao ,&nbsp;Manting Liu ,&nbsp;Sainiwaer Anwaier ,&nbsp;Xiang Long ,&nbsp;Ting You ,&nbsp;Zijian He ,&nbsp;Haotao Su ,&nbsp;Xinkui Zhang ,&nbsp;Jiaqi Wang ,&nbsp;Huanlei Huang ,&nbsp;Nanbo Liu ,&nbsp;Yujie Jiang ,&nbsp;Hongmo Xiang ,&nbsp;Yehuda G. Assaraf ,&nbsp;Xiaolan Zhu ,&nbsp;Xuelei Ma ,&nbsp;Qi Zhao ,&nbsp;Ping Zhu ,&nbsp;Lu Wang","doi":"10.1016/j.jconrel.2026.114697","DOIUrl":"10.1016/j.jconrel.2026.114697","url":null,"abstract":"<div><div>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<sup>+</sup> 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.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114697"},"PeriodicalIF":11.5,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134054","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}
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 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。
{"title":"Molecular engineering of designer diabetes therapeutics","authors":"Emily L. DeWolf,&nbsp;Bernice Webber,&nbsp;Matthew J. Webber","doi":"10.1016/j.jconrel.2026.114705","DOIUrl":"10.1016/j.jconrel.2026.114705","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114705"},"PeriodicalIF":11.5,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134056","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}
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 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。
{"title":"Engineering red blood cells for antigen-specific immune tolerance and personalized therapy of autoimmune diseases","authors":"Yeshuang Yuan ,&nbsp;Mengfan Yu ,&nbsp;Xingxing Zhu ,&nbsp;Wei Sun ,&nbsp;Jing Li ,&nbsp;Yiming Wang ,&nbsp;Shanbo Yang ,&nbsp;Yingying Shi ,&nbsp;Zhaolin Wang ,&nbsp;Xinyue Wang ,&nbsp;Fudi Wang ,&nbsp;Yue Xu ,&nbsp;Min Wang ,&nbsp;Jin Hu ,&nbsp;Bo Zhang ,&nbsp;Yudong Liu ,&nbsp;Xuan Zhang","doi":"10.1016/j.jconrel.2026.114681","DOIUrl":"10.1016/j.jconrel.2026.114681","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"392 ","pages":"Article 114681"},"PeriodicalIF":11.5,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134051","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}
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 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。
{"title":"A versatile self-adjuvanting macro-microporous ZIF-8@Mn MOF platform for efficient antigen capture and presentation to boost antitumor immunity","authors":"Qinhua Zuo, Linghong Huang, Yanping Wang, Yifan Cai, Yahui Chen, Chuanxu Zhu, Zonghua Liu, Kewei Wang, Wei Xue","doi":"10.1016/j.jconrel.2026.114707","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114707","url":null,"abstract":"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, Mn<sup>2+</sup> released from SOM-ZIF-8@Mn under TME conditions activates the STING pathway, promotes dendritic cell maturation and antigen cross-presentation, thereby activating CD8<sup>+</sup> 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.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"110 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134052","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}
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 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。
{"title":"Injectable hydrogel induces tumor cell extracellular calcification and bone regeneration to disrupt the osteolytic vicious cycle in bone metastasis","authors":"Minzhao Lin, Shaohui Deng, Simin Liang, Yujie Jiang, Qi Chen, Gengjia Chen, Bo Li, Yujun Cai, Xiaoxue Xie, Xintao Shuai, Zecong Xiao","doi":"10.1016/j.jconrel.2026.114701","DOIUrl":"https://doi.org/10.1016/j.jconrel.2026.114701","url":null,"abstract":"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 <em>in vitro</em> and <em>in vivo</em> 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.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"3 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134057","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}
引用次数: 0
期刊
Journal of Controlled Release
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1