Journal of Controlled Release最新文献_第4页

Gut microbiota perturbation and systemic inflammation are associated with salcaprozate sodium (SNAC)-enabled oral semaglutide delivery 肠道菌群紊乱和全身炎症与萨尔喀丙酸钠（SNAC）激活的口服西马鲁肽递送有关

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-09 DOI: 10.1016/j.jconrel.2026.114711

Amin Ariaee , Karim Noueihad , Alex Hunter , Anthony Wignall , Hannah R. Wardill , Maya Davies , Clive A. Prestidge , Paul Joyce

Semaglutide (SEM) is a glucagon-like peptide-1 (GLP-1) receptor agonist formulated for oral delivery with the absorption enhancer salcaprozate sodium (SNAC). Although oral SEM achieves 0.4–1% bioavailability through gastric epithelial uptake, gastrointestinal (GI) adverse events remain a major cause of therapy discontinuation. This study examined the effects of SEM (0.74 mg/kg/day), SNAC (22 mg/kg/day), and combined SEM–SNAC (1:33 w/w) treatments on microbiota and metabolic function, in healthy Sprague Dawley rats over 21 days. Whilst microbial α-diversity remained stable, SNAC significantly altered β-diversity (PERMANOVA, p < 0.05) and depleted primary fermenters in Muribaculaceae (−62%) and Bacteroidaceae (−77%) compared to the control group. These compositional changes correlated with reduced predicted saccharolytic enzyme abundance and fecal butyrate concentrations (−77% SNAC, −75% SEM–SNAC). Plasma cytokine analysis showed elevated tumor necrosis factor-α (TNF-α, 70%) and suppressed brain-derived neurotrophic factor (BDNF, 85%), consistent with changes in circulating inflammatory and neurotrophic markers from SNAC monotherapy. SNAC-treated animals also exhibited increased liver weight and reduced caecum mass, occurring alongside microbiota compositional changes and altered fermentation-associated markers. Spearman correlations linked Muribaculaceae and Bacteroidaceae loss with decreased saccharolytic enzyme abundance, lower SCFA levels, and increased TNF-α. While these findings are associative and require mechanistic validation, they indicate that chronic SNAC exposure is linked to concurrent microbial, metabolic, and inflammatory marker changes in healthy rats, highlighting the potential need for alternative, microbiota-safe strategies for oral peptide delivery.

Semaglutide （SEM）是一种胰高血糖素样肽-1 （GLP-1）受体激动剂，与吸收促进剂salcaprozate钠（SNAC）一起口服。尽管口服SEM通过胃上皮摄取可达到0.4-1%的生物利用度，但胃肠道（GI）不良事件仍然是中断治疗的主要原因。本研究检测了SEM（0.74 mg/kg/day）、SNAC（22 mg/kg/day）和SEM - SNAC （1:33 w/w）联合处理对健康Sprague Dawley大鼠21 天内微生物群和代谢功能的影响。虽然微生物α-多样性保持稳定，但与对照组相比，SNAC显著改变了Muribaculaceae（- 62%）和Bacteroidaceae（- 77%）的β-多样性（PERMANOVA, p <； 0.05），并减少了初级发酵剂。这些成分变化与预测的糖分解酶丰度和粪便丁酸盐浓度降低相关（- 77% SNAC, - 75% SEM-SNAC）。血浆细胞因子分析显示肿瘤坏死因子-α (TNF-α, 70%)升高，脑源性神经营养因子（BDNF, 85%）抑制，与SNAC单药治疗后循环炎症和神经营养标志物的变化一致。snac处理的动物还表现出肝脏重量增加和盲肠质量减少，同时微生物群组成发生变化和发酵相关标记物发生改变。Spearman相关性将Muribaculaceae和Bacteroidaceae的损失与糖溶酶丰度降低、SCFA水平降低和TNF-α升高联系起来。虽然这些发现是相关的，需要机制验证，但它们表明，慢性SNAC暴露与健康大鼠的微生物、代谢和炎症标志物的同步变化有关，这突出了口服肽递送的替代、微生物安全策略的潜在需求。

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引用次数: 0

Engineered cargo-free nanoparticle decoys for phagocytic modulation of macrophages 用于巨噬细胞吞噬调节的工程无货纳米颗粒诱饵

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-09 DOI: 10.1016/j.jconrel.2026.114699

Peyton M. Panovich , Aditi Ganesan , Arianna I. Markey , Miriam E. Stevens , Owen M. Kelly , Alexandra S. Piotrowski-Daspit

Polymeric nanoparticles (NPs) are a versatile delivery platform for non-viral genetic therapies. However, a key shortcoming of polymeric NPs (and other non-viral delivery vehicles) is the often-high accumulation of NPs within the liver and the spleen after systemic intravenous (IV) administration in vivo. This phenomenon is largely the result of the mononuclear phagocytic system (MPS), a class of phagocytic cells responsible for native immune response and toxin clearance within the body. One strategy to overcome NP clearance by the MPS is the use of phagocytic modulating pre-treatments to intentionally and temporarily alter the phagocytic behavior of macrophages such that sequentially administered therapeutic NPs can be delivered to extrahepatic and extrasplenic tissues. Here, we explore the use cargo-free poly(lactic-co-glycolic acid) (PLGA) “decoy” NPs as pre-treatments for phagocytic evasion of sequentially administered therapeutic NPs. Analysis via flow cytometry and fluorescence microscopy reveal that cargo-free PLGA NPs significantly decrease uptake of subsequently administered therapeutic NPs by macrophages. Specifically, we conclude that variables such as size, surfactant composition, and timing of pre-treatment influence the behavior of cargo-free PLGA decoy NPs in modulating phagocytic activity of macrophages. In in vivo studies, we report decreased accumulation in the liver and increased deposition of therapeutic NPs in the lung with pre-administration of cargo-free decoy PLGA NPs. Together, these studies suggest pre-treatment with decoy NPs can reduce therapeutic NP clearance, with the potential to improve nanomedicine delivery capabilities for a wide range of therapeutics and disease targets.

聚合纳米颗粒（NPs）是一种通用的非病毒基因治疗递送平台。然而，聚合物NPs（和其他非病毒递送载体）的一个主要缺点是，在体内全身静脉（IV）给药后，NPs在肝脏和脾脏内的积累往往很高。这种现象主要是单核吞噬系统（MPS）的结果，这是一类吞噬细胞，负责体内的天然免疫反应和毒素清除。克服MPS清除NP的一种策略是使用吞噬调节预处理来有意和暂时改变巨噬细胞的吞噬行为，以便顺序给予治疗性NP可以递送到肝外和脾外组织。在这里，我们探索使用无货物聚（乳酸-羟基乙酸）（PLGA）“诱饵”NPs作为预先处理的吞噬逃避顺序给药的治疗性NPs。通过流式细胞术和荧光显微镜分析显示，无货物PLGA NPs显著减少巨噬细胞随后给予治疗性NPs的摄取。具体而言，我们得出结论，诸如大小，表面活性剂组成和预处理时间等变量影响无货物PLGA诱饵NPs调节巨噬细胞吞噬活性的行为。在体内研究中，我们报告了在预先施用无货物诱饵PLGA NPs的情况下，治疗性NPs在肝脏中的积累减少，在肺部的沉积增加。总之，这些研究表明，用诱饵NP进行预处理可以减少治疗性NP的清除率，从而有可能提高纳米药物对广泛治疗方法和疾病靶点的递送能力。

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引用次数: 0

Corrigendum to ‘A LDL-masked liposomal-doxorubicin reverses drug resistance in human cancer cells’ [Journal of Controlled Release 149(2) (2011) 196–205] “低密度脂蛋白掩盖脂质体-阿霉素逆转人类癌细胞的耐药性”的更正[Journal of control Release 149(2) (2011) 196-205]

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-09 DOI: 10.1016/j.jconrel.2026.114675

Joanna Kopecka , Ivana Campia , Paolo Olivero , Gianpiero Pescarmona , Dario Ghigo , Amalia Bosia , Chiara Riganti

引用次数: 0

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

Journal of Controlled Release

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。

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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

Journal of Controlled Release

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。

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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

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