Journal of Controlled Release最新文献_第4页

Ultrasmall zwitterion-micelles coupled with anti-checkpoint antibody for overcoming glioma barriers to eliminate stem cells and amplify immunotherapy 超小两性离子胶束结合抗检查点抗体克服胶质瘤障碍消除干细胞和扩大免疫治疗

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-04-10 Epub Date: 2026-01-28 DOI: 10.1016/j.jconrel.2026.114668

Ke Wang , Yi Wang , Dongyu Zhang , Bingbing Zhao , Shineng Chen , Yinan Zhong , Dechun Huang , Hongliang Qian , Hao Xie , Wei Chen

The efficacy of immune checkpoint blockade (ICB) against glioblastoma (GBM) is significantly constrained by the blood-brain barrier (BBB) and the immunosuppressive tumor microenvironment associated with glioma stem cells (GSCs). To address these challenges, anti-programmed death-ligand 1 antibodies (anti-PD-L1) are conjugated to ultra-small zwitterionic micelles (MCB) through pH-sensitive traceless linkers, followed by encapsulation of salinomycin (SAL) to construct multimodal zwitterionic micelles (MCB-PD@S). The resulting micelles efficiently cross the BBB via BGT-1-mediated active transport, exploit vesicular trafficking pathways in GBM vasculature for tumor-specific accumulation, and utilize their zwitterionic surface to enhance penetration into GSC niches through monocarboxylate transporters (MCTs). SAL-induced eradication of GSCs robustly stimulates immunogenic cell death, dendritic cell maturation, and subsequent T-cell activation. This effect is synergistically amplified by the release of structurally intact anti-PD-L1 within the acidic tumor microenvironment, collectively fostering potent and sustained antitumor immunity that effectively suppresses GBM recurrence. This work establishes a new paradigm in brain tumor therapy by simultaneously overcoming biological delivery barriers and immune evasion, offering a clinically translatable solution for post-resection GBM management.

免疫检查点阻断（ICB）对胶质母细胞瘤（GBM）的疗效受到血脑屏障（BBB）和与胶质瘤干细胞（GSCs）相关的免疫抑制肿瘤微环境的显著限制。为了解决这些挑战，anti-programmed death-ligand 1抗体（anti-PD-L1）通过ph敏感的无迹连接物偶联到超小两性胶束（MCB）上，然后包封盐霉素（SAL）构建多模态两性胶束（MCB-PD@S）。由此产生的胶束通过bgt -1介导的主动运输有效地穿过血脑屏障，利用GBM脉管系统中的囊泡运输途径进行肿瘤特异性积累，并利用其两性离子表面通过单羧酸转运体（mct）增强对GSC壁龛的渗透。sal诱导的GSCs的根除强烈刺激免疫原性细胞死亡、树突状细胞成熟和随后的t细胞活化。这种作用通过在酸性肿瘤微环境中释放结构完整的抗pd - l1而协同放大，共同促进有效和持续的抗肿瘤免疫，有效抑制GBM复发。这项工作建立了脑肿瘤治疗的新范式，同时克服了生物传递障碍和免疫逃避，为切除后GBM的治疗提供了临床可翻译的解决方案。

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引用次数: 0

Dendritic cell-targeted tumor antigen delivery by glucosylated lipid nanoparticles for precision tumor immunotherapy 糖基化脂质纳米颗粒用于精确肿瘤免疫治疗的树突状细胞靶向肿瘤抗原递送

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-04-10 Epub Date: 2026-01-28 DOI: 10.1016/j.jconrel.2026.114671

Jing Liu , Fengyi Lin , Guanghao Hu , Ruixin Zhang , Changyang Gong , Xun Sun , Peng Mi

Vaccination is an important approach for cancer immunotherapy, but is limited by the inefficient delivery of immunogenic antigens to dendritic cells (DCs) to stimulate tumor-specific immune responses. Herein, we engineered glucosylated lipid nanoparticles (GluLNPs) to deliver tumor antigens and form personalized vaccines in situ, efficiently targeting DCs to stimulate robust antitumor immunity for the immunotherapy of low-immunogenic breast cancer. Through intratumoral injection, GluLNPs can efficiently capture and deliver tumor antigens, including neoantigens released from eradicated primary triple-negative breast tumors after mild phototherapy with photosensitizer-loaded nanoparticles (i.e., ICGNPs), to DCs, thereby triggering DC maturation and robust antitumor immune responses. Moreover, GluLNPs can effectively elicit strong systemic antitumor immunity against distant and metastatic triple-negative breast tumors when combined with immune checkpoint blockade. This study presents a practical strategy for developing effective DC-targeting personalized nanovaccines and in situ vaccination for precise and effective tumor immunotherapy.

疫苗接种是癌症免疫治疗的一种重要方法，但由于将免疫原性抗原递送到树突状细胞（dc）以刺激肿瘤特异性免疫反应的效率低下而受到限制。在此，我们设计了糖基化脂质纳米颗粒（GluLNPs）来递送肿瘤抗原并原位形成个性化疫苗，有效地靶向dc，以刺激低免疫原性乳腺癌的强大抗肿瘤免疫。通过瘤内注射，GluLNPs可以有效地捕获肿瘤抗原，并将肿瘤抗原（包括经轻度光敏剂负载纳米颗粒（即ICGNPs）光疗后从根除的原发性三阴性乳腺肿瘤中释放的新抗原）递送到DC，从而触发DC成熟和强大的抗肿瘤免疫反应。此外，当GluLNPs与免疫检查点阻断联合使用时，可以有效地引发对远处和转移性三阴性乳腺肿瘤的强全身抗肿瘤免疫。本研究提出了一种实用的策略，用于开发有效的dc靶向个性化纳米疫苗和原位疫苗，以实现精确有效的肿瘤免疫治疗。

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引用次数: 0

Long-acting nanomedicine for brain diseases 脑疾病长效纳米药物

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-04-10 Epub Date: 2026-01-28 DOI: 10.1016/j.jconrel.2026.114665

Jun Liao , Qi Huang , Ruiyu Li , Lidong Gong , Tiancheng Li , Zhiqiang Lin

Effective pharmacological management of neurological disorders is profoundly limited by the blood-brain barrier (BBB) and the short biological half-life of therapeutics, necessitating frequent and invasive administration. Long-acting drug delivery systems (LADDS) integrated with nanotechnology offer a transformative paradigm to overcome these challenges. This review discusses the key principles and nanoplatforms enabling sustained brain drug delivery to the central nervous system. Key release mechanisms are analyzed including diffusion, degradation, and stimuli-responsiveness which alongside a survey of major nanocarrier platforms, designed to achieve controlled pharmacokinetics and enhanced BBB penetration. Recent groundbreaking applications in preclinical models of ischemic stroke, Alzheimer's disease, glioma, and traumatic brain injury are highlighted, where LADDS provide continuous, localized neuroprotection and modulate chronic pathology. Finally, the significant translational challenges, including long-term biocompatibility, manufacturing scalability, and regulatory hurdles, are critically evaluated. LADDS are poised to redefine neuropharmacology, shifting the focus from transient symptom management to precise, durable, and restorative intervention for chronic brain diseases.

神经系统疾病的有效药物管理受到血脑屏障（BBB）和治疗药物的生物半衰期短的严重限制，需要频繁和侵入性的给药。结合纳米技术的长效给药系统（LADDS）为克服这些挑战提供了一种变革性的范例。这篇综述讨论了关键原理和纳米平台，使大脑药物持续传递到中枢神经系统。分析了主要的释放机制，包括扩散、降解和刺激反应，以及主要纳米载体平台的调查，旨在实现控制药代动力学和增强血脑屏障渗透。最近在缺血性中风、阿尔茨海默病、胶质瘤和创伤性脑损伤的临床前模型中的突破性应用得到了强调，在这些模型中，LADDS提供了持续的、局部的神经保护和调节慢性病理。最后，对重大的转化挑战，包括长期生物相容性、制造可扩展性和监管障碍进行了批判性评估。LADDS有望重新定义神经药理学，将重点从短暂症状管理转移到慢性脑疾病的精确、持久和恢复性干预。

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引用次数: 0

Selective tumor lysis by charge-alternating spherical membrane-lytic peptide bottlebrushes via redox backbone degradation and pH-gated unmasking 电荷交替球形膜解肽瓶刷通过氧化还原主干降解和ph门控解掩膜的选择性肿瘤裂解

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-04-10 Epub Date: 2026-02-05 DOI: 10.1016/j.jconrel.2026.114692

Lubin Ning , Rui Xu , Chaoke Qin , Lei Sun , Liming Shao , Hongrui Zhang , Li Yan , Gengzhi Ren , Xiuying Sun , Hao Chang , Xiangdong Cheng , Fie Jia

The clinical utility of membrane-lytic peptides (MLPs) as cancer therapeutics is severely compromised by their inherent instability, rapid clearance, and non-specific toxicity, including hemolysis. We report a unimolecular nanoparticle platform, the Charge-Alternating Spherical MLP (CAS-MLP), engineered to overcome these barriers through a synergistic structural and chemical design. Structurally, MLPs are grafted as side chains onto a redox-responsive poly(disulfide) backbone, forming a bottlebrush architecture that enhances proteolytic stability and prolongs circulation. Chemically, the MLPs' lytic activity is temporarily neutralized using detachable charge-alternating (CA) reagents via maleamic anhydride-amine chemistry. This “smart” shielding minimizes hemolysis and off-target toxicity while also serving as a conjugation point for cancer-specific ligands, enabling precisely tuned targeting. This platform is designed for sequential intracellular activation: after ligand-mediated uptake, the acidic endosomal environment triggers CA reagent detachment, while the reductive cytosol degrades the poly(disulfide) backbone. This dual-stimuli-triggered disassembly selectively restores the MLP's lytic function inside the cancer cell. In vivo, the CAS-MLP platform demonstrates potent tumor growth suppression with negligible side effects. By leveraging the abundant lysine residues of MLPs, this approach provides a versatile and effective solution to key challenges in MLP-based therapy.

由于其固有的不稳定性、快速清除和非特异性毒性（包括溶血），膜溶肽（MLPs）作为癌症治疗药物的临床应用受到严重损害。我们报道了一种单分子纳米粒子平台，即电荷交替球形MLP (CAS-MLP)，通过协同结构和化学设计克服了这些障碍。在结构上，mlp作为侧链接枝到氧化还原反应的聚二硫骨架上，形成一个瓶刷结构，增强蛋白水解稳定性并延长循环时间。化学上，通过马来酸酐-胺化学，使用可分离的电荷交替（CA）试剂暂时中和MLPs的裂解活性。这种“智能”屏蔽可以最大限度地减少溶血和脱靶毒性，同时也可以作为癌症特异性配体的缀合点，从而实现精确调谐靶向。该平台设计用于连续的细胞内激活：在配体介导的摄取后，酸性内体环境触发CA试剂脱离，而还原性细胞质降解聚二硫烷骨架。这种双重刺激触发的分解选择性地恢复了MLP在癌细胞内的裂解功能。在体内，CAS-MLP平台显示出有效的肿瘤生长抑制作用，副作用可以忽略不计。通过利用mlp丰富的赖氨酸残基，该方法为mlp治疗中的关键挑战提供了一种通用且有效的解决方案。

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引用次数: 0

A robust RNAi nanoplatform for precise activation of cGAS-STING pathway and effective immune checkpoint blockade to potentiate cancer immunotherapy 一个强大的RNAi纳米平台，用于精确激活cGAS-STING途径和有效的免疫检查点阻断，以增强癌症免疫治疗

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-04-10 Epub Date: 2026-02-06 DOI: 10.1016/j.jconrel.2026.114690

Lei Xu , Zhuoshan Huang , Wenyue Zhang , Yuan Cao , Xiaotang Guo , Bo Hu , Rong Li , Qiusheng Lan , Xiaoding Xu

Activation of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-interferon gene stimulator (STING) pathway has demonstrated significant potential in cancer treatment due to its crucial role in bridging the innate and adaptive immunity. However, clinical attempts of current cGAS-STING activating approaches remain challenged because of their undesired adverse effects and low therapeutic efficacy. We herein developed a new and robust immunostimulatory RNA interfering (RNAi) nanoplatform to potentiate breast cancer (BCa) immunotherapy through precise activation of cGAS-STING pathway and effective immune checkpoint blockade. This nanoplatform comprises the electrostatic complexes of small interfering RNA (siRNA) targeting oncogene coactivator-associated arginine methyltransferase 1 (Carm1) and metformin prodrug. Using orthotopic and metastatic BCa tumors, we demonstrated this nanoplatform could suppress the proliferation of BCa cells via siRNA-mediated Carm1 silencing and down-regulate programmed death-ligand 1 (PD-L1) expression via metformin-mediated ubiquitin-proteasome degradation. More importantly, due to the important role of oncogene Carm1 in repairing damaged double stand DNA (dsDNA), Carm1 silencing could specifically enhance the accumulation of damaged dsDNA and cytosolic release of dsDNA fragments to precisely activate the cGAS-STING pathway in BCa cells, which could thus promote their expression and secretion of interferon-β (IFN-β) to induce a significant inhibition of BCa tumor growth via leveraging both the innate and adaptive immunity.

环鸟苷单磷酸-腺苷单磷酸合成酶(cGAS)-干扰素基因刺激因子（STING）通路的激活由于其在先天免疫和适应性免疫之间的桥梁作用而在癌症治疗中显示出巨大的潜力。然而，目前cGAS-STING激活方法的临床尝试仍然面临挑战，因为它们的不良反应和低疗效。我们在此开发了一种新的强大的免疫刺激RNA干扰（RNAi）纳米平台，通过精确激活cGAS-STING途径和有效的免疫检查点阻断来增强乳腺癌（BCa）的免疫治疗。该纳米平台由靶向癌基因共激活子相关精氨酸甲基转移酶1 （Carm1）和二甲双胍前药的小干扰RNA （siRNA）静电复合物组成。在原位和转移性BCa肿瘤中，我们证明了这种纳米平台可以通过sirna介导的Carm1沉默抑制BCa细胞的增殖，并通过二甲双胍介导的泛素蛋白酶体降解下调程序性死亡配体1 （PD-L1）的表达。更重要的是，由于癌基因Carm1在修复受损双支架DNA （dsDNA）中的重要作用，沉默Carm1可以特异性地增强受损dsDNA的积累和dsDNA片段的胞质释放，从而精确激活BCa细胞中的cGAS-STING通路，从而促进其干扰素-β (IFN-β)的表达和分泌，通过先天免疫和适应性免疫共同作用，诱导BCa肿瘤生长受到显著抑制。

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引用次数: 0

Pathology-responsive light-triggered conjunctival adhesive implantable hydrogels for effective anti-scarring after glaucoma filtering surgery 病理反应性光触发结膜黏附植入式水凝胶用于青光眼滤过术后有效抗瘢痕形成

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-04-10 Epub Date: 2026-01-30 DOI: 10.1016/j.jconrel.2026.114677

Xianmin Shi , Zijun Lin , Danni Xiao, Wanzhen Li, Jue Wang, Yuanfeng He, Conghan Wang, Gengsheng Ye, Yao Liu, Yanjuan Huang, Chunshun Zhao

Glaucoma filtration surgery (GFS) frequently fails due to uncontrolled subconjunctival scarring, driven by a cascade of postoperative inflammation, oxidative stress, and exaggerated myofibroblast activation. To address this, we developed an in-situ light-triggered hydrogel that enables strong conjunctival adhesion, bleb mechanical support, and pathology-responsive smart drug delivery for effective bleb scarring inhibition. The crosslinked hydrogel system prepared from functionalized carboxymethyl chitosan and epigallocatechin gallate (EGCG), prior to ultraviolet light (UV) exposure, was denoted as PNE hydrogel. After injection, PNE can adapt to ocular anatomy, and subsequent transconjunctival light exposure rapidly activates hydrogel crosslinking and covalent tissue adhesion, generating a mechanically robust hydrogel, denoted as PNE-UV hydrogel. Meanwhile, light-induced surface property changes further enhance conjunctival adhesion and reduce interface inflammatory cell infiltration. Concurrently, light-induced hydrophilic-to-hydrophobic hydrogel surface transition promotes water exclusion, further enhancing tissue adhesion to minimize interface inflammatory cell infiltration. With adequate mechanical strength, rapid self-healing, and good biosafety, PNE-UV provides essential mechanical bleb support during wound healing. Crucially, elevated postoperative reactive oxygen species (ROS) triggers intelligent EGCG release for over 17 days, which not only effectively scavenges ROS and promotes macrophage M1-to-M2 polarization to mitigate inflammation, but also suppresses TGF-β1-induced conjunctival fibroblast-to-myofibroblast transdifferentiation and myofibroblast proliferation. In a rabbit model of filtration surgery, PNE-UV hydrogel significantly prolonged bleb survival, reduced intraocular pressure, and decreased collagen deposition via mitigating oxidative stress and inflammation and suppressing fibrotic processes. Collectively, this interfacial adhesion and precise immunomodulation hydrogel presents an effective and clinically translatable strategy for post-GFS scarring prevention.

青光眼滤过手术（GFS）经常因结膜下瘢痕不受控制而失败，这是由术后炎症、氧化应激和肌成纤维细胞激活的级联反应驱动的。为了解决这个问题，我们开发了一种原位光触发水凝胶，它具有很强的结膜粘附性，水泡机械支持和病理反应智能药物递送，可有效抑制水泡瘢痕形成。将羧甲基壳聚糖与表没食子儿茶素没食子酸酯（EGCG）经紫外线照射制备的交联水凝胶体系命名为PNE水凝胶。PNE注射后能够适应眼部解剖结构，随后经结膜光照射迅速激活水凝胶交联和共价组织粘连，生成机械坚固的水凝胶，称为PNE- uv水凝胶。同时，光诱导的表面性质变化进一步增强结膜粘连，减少界面炎症细胞浸润。同时，光诱导的亲水性到疏水性的水凝胶表面转变促进了水的排斥，进一步增强了组织粘连，减少了界面炎症细胞的浸润。PNE-UV具有足够的机械强度，快速自愈和良好的生物安全性，在伤口愈合过程中提供必要的机械气泡支持。至关重要的是，术后活性氧（ROS）升高触发EGCG智能释放超过17天，不仅有效清除ROS，促进巨噬细胞m1 - m2极化减轻炎症，而且抑制TGF-β1诱导的结膜成纤维细胞向肌成纤维细胞转分化和肌成纤维细胞增殖。在兔滤过手术模型中，PNE-UV水凝胶通过减轻氧化应激和炎症以及抑制纤维化过程，显著延长水泡存活时间，降低眼压，减少胶原沉积。总的来说，这种界面粘附和精确的免疫调节水凝胶为gfs后疤痕预防提供了一种有效的临床可翻译策略。

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引用次数: 0

Non-invasive administration of exosomes 非侵入性外泌体给药

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-04-10 Epub Date: 2026-02-03 DOI: 10.1016/j.jconrel.2026.114674

Teertha Ayanji , Na Yan , Litian Jia , Ke Cheng

Exosomes, as naturally derived extracellular vesicles, have emerged as promising therapeutic carriers due to their intrinsic biocompatibility, low immunogenicity, and ability to facilitate intercellular communication. In recent years, the non-invasive administration of exosomes has gained increasing attention as a strategy to enhance patient compliance and improve drug delivery efficiency while circumventing the limitations associated with traditional invasive routes. This review provides a comprehensive overview of the non-invasive delivery of exosome-based therapeutics, spanning oral, intranasal, inhalation, ocular, and transdermal administration. Moreover, we discuss underexplored pathways with unique anatomical and physiological advantages for systemic and local therapy, including sublingual, otic, rectal, and vaginal delivery. Each administration route will outline the key anatomic and biological barriers that exosomes must overcome, along with commonly employed strategies to address them. We further explore the therapeutic potential of non-invasive exosome delivery across various diseases, highlighting the advantages and limitations of each approach. Finally, we discuss the current challenges in translating non-invasive exosome delivery into clinical practice and propose future directions to advance this goal.

外泌体作为天然来源的细胞外囊泡，由于其内在的生物相容性、低免疫原性和促进细胞间通讯的能力，已成为有希望的治疗载体。近年来，外泌体的非侵入性给药越来越受到关注，作为一种提高患者依从性和提高药物递送效率的策略，同时规避了传统侵入性途径的局限性。这篇综述提供了基于外泌体的非侵入性治疗的全面概述，包括口服、鼻内、吸入、眼内和透皮给药。此外，我们还讨论了在全身和局部治疗中具有独特解剖和生理优势的未被探索的途径，包括舌下、耳、直肠和阴道分娩。每种给药途径将概述外泌体必须克服的关键解剖学和生物学障碍，以及解决这些障碍的常用策略。我们进一步探讨了非侵入性外泌体在各种疾病中的治疗潜力，强调了每种方法的优点和局限性。最后，我们讨论了将非侵入性外泌体递送转化为临床实践的当前挑战，并提出了推进这一目标的未来方向。

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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 : 2026-04-10 Epub 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

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 : 2026-04-10 Epub 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

Sonocatalytic multifunctional hydrogel in-situ remodels the infectious microenvironment for eradicating refractory osteomyelitis 声催化多功能水凝胶原位重建难治性骨髓炎的感染微环境

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-04-10 Epub Date: 2026-02-06 DOI: 10.1016/j.jconrel.2026.114686

Xingzi He , Yaping Li , Zhihui Xiang , Yifan Wu , Jinfeng Zhou , Peng Tang , Xiaoxiao Ji , Zhongming Huang , Jianbin Xu , Wei Wang , Yiying Qi

Osteomyelitis remains a formidable clinical challenge due to biofilm-associated antibiotic resistance, a hypoxic and immunosuppressive microenvironment, and progressive inflammatory bone destruction. To address these multifactorial barriers, we developed an ultrasound (US)-activatable injectable hydrogel, designated MIL-101(Fe)@ZnO@MM + PFO + Gel, which integrates sonodynamic catalysis, oxygen regulation, and immunomodulation within a single therapeutic platform. The core–shell nanostructure comprises MIL-101(Fe)@ZnO nanoflowers, synthesized via a seed-mediated growth process to couple the redox activity of iron with the peroxidase-like catalytic properties of ZnO. The core–shell nanostructure comprises MIL-101(Fe)@ZnO nanoflowers, synthesized via a seed-mediated growth process to couple the redox activity of iron with the peroxidase-like catalytic properties of ZnO. These nanozymes are camouflaged with a thiolated macrophage membrane (MM), dispersed in oxygen-enriched perfluorocarbon (PFO), and crosslinked within a quaternary ammonium-modified hydrogel matrix possessing biofilm-penetrating capability. Upon US irradiation, the hydrogel achieves deep biofilm penetration and generates abundant reactive oxygen species (ROS) through Fe/Zn synergistic catalysis, while PFO liquefaction releases oxygen to alleviate local hypoxia and potentiate the sonodynamic effect. In a rat model of methicillin-resistant Staphylococcus aureus (MRSA)-induced tibial osteomyelitis, this treatment markedly reduced bacterial load, substantially suppressed inflammatory infiltration and pro-inflammatory cytokine cascades, and effective mitigation of bone erosion. Collectively, MIL-101(Fe)@ZnO@MM + PFO + Gel+US offers a minimally invasive, spatiotemporally controlled platform for eradicating refractory infections and reprogramming the osteomyelitic microenvironment toward regeneration.

由于生物膜相关的抗生素耐药性、缺氧和免疫抑制微环境以及进行性炎症性骨破坏，骨髓炎仍然是一个巨大的临床挑战。为了解决这些多因素障碍，我们开发了一种超声（US）可激活注射水凝胶，命名为MIL-101(Fe)@ZnO@MM + PFO + Gel，它在单一治疗平台中集成了声动力催化，氧调节和免疫调节。该核壳纳米结构由MIL-101(Fe)@ZnO纳米花组成，通过种子介导的生长过程合成，将铁的氧化还原活性与ZnO的过氧化物酶催化性能结合起来。该核壳纳米结构由MIL-101(Fe)@ZnO纳米花组成，通过种子介导的生长过程合成，将铁的氧化还原活性与ZnO的过氧化物酶催化性能结合起来。这些纳米酶被巯基化巨噬细胞膜（MM）伪装，分散在富氧全氟碳（PFO）中，并在具有生物膜穿透能力的季铵修饰水凝胶基质中交联。经US照射后，水凝胶通过Fe/Zn协同催化深层穿透生物膜，产生丰富的活性氧（ROS），而PFO液化释放氧气，缓解局部缺氧，增强声动力效应。在耐甲氧西林金黄色葡萄球菌（MRSA）诱导的胫骨骨髓炎大鼠模型中，这种治疗显著降低了细菌负荷，显著抑制了炎症浸润和促炎细胞因子级联反应，并有效缓解了骨侵蚀。总的来说，MIL-101(Fe)@ZnO@MM + PFO + Gel+US提供了一个微创、时空可控的平台，用于根除难治性感染和重新编程骨髓炎微环境以实现再生。

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