Journal of Controlled Release最新文献_第5页

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

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

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

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

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

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

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引用次数: 0

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

IF 10.8 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

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

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

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

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

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引用次数: 0

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

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

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

Qiyong Guo, Weihang Cao, Ling Chen

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

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

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引用次数: 0

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

IF 10.8 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

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

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

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

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

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引用次数: 0

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

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

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

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

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

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

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引用次数: 0

Unlocking component-level chemical structural information for AI-driven targeted nanoparticle design 为人工智能驱动的靶向纳米颗粒设计解锁组件级化学结构信息

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-06 DOI: 10.1016/j.jconrel.2026.114704

Haomin Wu , Yu Cheng , Yuanhui Ji

The structural complexity and unpredictable in vivo fate of nanoparticles pose major barriers to rational design of targeted nanoparticles. The rapidly developing artificial intelligence (AI) technology brings new opportunities to establish structure-property relationships. However, the effectiveness of AI-based prediction models is still constrained by the absence of nanoparticle compositional representation. To address this, we innovatively developed component-level image-based structural descriptors (CISD) and integrated them into the nanoparticle biodistribution prediction model. Our framework addresses several challenges in generating representations of nanoparticle compositions, such as data scarcity, poor generalizability across different nanoparticle types, and limited interpretability. Therefore, our work provides a tool that bridges the chemical structural information of nanoparticle components with representations usable by machine learning. In independent cross-domain validation, our developed predictive model significantly outperformed the traditional frameworks that rely solely on nanoparticle characteristics and biodistribution experimental parameters, with an R² increase of 0.25 and an RMSE reduction of 3.22. Leveraging SHapley Additive exPlanations (SHAP) analysis and hook functions, we disentangled multi-level structure-property relationships, with CISD enhancing tunable factors in nanoparticle design. Building upon the extracted structure-property relationships and model projections, we achieved up to a 12.66-fold enhancement in predicted biodistribution values. In the future, synergistic integration with advanced algorithms like generative AI holds promise not merely for curtailing animal experimentation, but for pioneering closed-loop inverse design systems to rationally screen a wider range of potential structures of nanoparticle components and nanoparticle physicochemical attributes.

纳米粒子结构的复杂性和不可预测的体内命运是合理设计靶向纳米粒子的主要障碍。快速发展的人工智能技术为建立结构-性质关系带来了新的机遇。然而，基于人工智能的预测模型的有效性仍然受到缺乏纳米颗粒成分表示的限制。为了解决这个问题，我们创新地开发了组件级基于图像的结构描述符（CISD），并将其集成到纳米颗粒生物分布预测模型中。我们的框架解决了在生成纳米颗粒组成表示方面的几个挑战，例如数据稀缺性、不同纳米颗粒类型之间的较差泛化性以及有限的可解释性。因此，我们的工作提供了一种工具，将纳米颗粒成分的化学结构信息与机器学习可用的表示连接起来。在独立的跨域验证中，我们开发的预测模型显著优于仅依赖纳米颗粒特征和生物分布实验参数的传统框架，R2增加0.25，RMSE降低3.22。利用SHAP分析和钩子函数，我们解开了多层次的结构-性质关系，CISD增强了纳米颗粒设计中的可调因子。在提取的结构-性质关系和模型预测的基础上，我们实现了预测生物分布值的12.66倍增强。在未来，与生成式人工智能等先进算法的协同集成不仅有望减少动物实验，而且有望开创闭环逆设计系统，以合理筛选纳米颗粒成分的更广泛的潜在结构和纳米颗粒的物理化学属性。

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引用次数: 0

Curcumin driven formation of self-cascade nanoclusters from urate oxidase-H2S donor conjugates for acute gouty arthritis alleviation 姜黄素驱动尿酸氧化酶- h2s供体偶联物自级联纳米簇的形成缓解急性痛风性关节炎

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-06 DOI: 10.1016/j.jconrel.2026.114696

Yuxuan Ge , Fan Rong , Zixin Wang , Yujia Lu , Yanwen Zhang , Yijun Cheng , Junsheng Chen , Yin Wang

Gouty arthritis (GA) is a common arthritis characterized by chronic inflammation and monosodium urate (MSU) crystal deposition in articular structures. Current clinical medications mainly target to alleviate the inflammation, but do less to the deposited MSU. Although administration of urate oxidase (UOx) could degrade the MSU, the toxic by-product hydrogen peroxide (H₂O₂) generated during the degradation would aggravate the inflammation. To surmount this, we developed a smart stimuli-responsive drug delivery platform (termed UBC) for the treatment of acute GA, where urate oxidase (UOx) was initially modified with the phenylboronic acid-based self-immolative thiocarbamate through nucleophilic substitution, and then co-assembled with curcumin through boronate bonds. This way, the platform could not only directly eliminate MSU, but also release the therapeutic agents, hydrogen sulfide (H₂S) gas and curcumin, triggered by the toxic by-product H₂O₂ during UOx catalysis. Thus, the inflammation could be effectively restrained by the in situ co-delivery of H₂S and curcumin. We believe this strategy provides a novel approach for the treatment of inflammation-related diseases and novel insight into the construction of multi-functional therapeutic nanomaterials from enzymes or other biomolecules.

痛风性关节炎（GA）是一种常见的关节炎，以慢性炎症和尿酸钠（MSU）晶体沉积在关节结构中为特征。目前的临床药物主要针对炎症的缓解，而对沉积的MSU作用较少。虽然使用尿酸氧化酶（UOx）可以降解MSU，但降解过程中产生的有毒副产物过氧化氢（H2O2）会加重炎症。为了克服这一问题，我们开发了一种用于治疗急性GA的智能刺激反应药物递送平台（称为UBC），其中尿酸氧化酶（UOx）最初通过亲核取代被苯基硼酸基自焚硫氨基甲酸酯修饰，然后通过硼酸键与姜黄素共组装。这样，该平台不仅可以直接消除MSU，还可以释放由UOx催化的有毒副产物H2O2引发的治疗剂硫化氢（H2S）气体和姜黄素。因此，H2S和姜黄素的原位共递送可以有效地抑制炎症反应。我们相信这一策略为炎症相关疾病的治疗提供了一种新的方法，并为从酶或其他生物分子构建多功能治疗纳米材料提供了新的见解。

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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 : 2026-02-06 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

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 : 2026-02-06 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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引用次数: 0

A precision nitric oxide-releasing hydrogel promoting nanoparticles permeation for comprehensive nerve-vessel recovery and microenvironment regulation in diabetic wounds 一种精密一氧化氮释放水凝胶，促进纳米颗粒渗透，用于糖尿病伤口的神经血管全面恢复和微环境调节

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-06 DOI: 10.1016/j.jconrel.2026.114703

Enhao Lu , Xueli Huang , Qi Zhang , Kuankuan Luo , Xin Yan , Weimin Nie , Lingmin Zhang , Ruining Hu , Jing Bian , Yue Li , Yu Luo , Zhiwen Zhang , Jing Zhao , Xianyi Sha

Peripheral neuropathy and microcirculation distribution are key causes of diabetic foot ulcers (DFUs). Based on the vessel dilation and nerve regeneration effect of nitric oxide (NO), a multi-functional nanoparticles-hydrogel therapy system was developed in this research. In order to inhibit the side effect of NO which could form peroxynitrite anions (ONOO⁻) and lead to cytotoxicity, dual strategies were purposed, including physiologic NO generation and combination therapy with anti-oxidation. This kind of in situ NO generation was also proved to accelerate the permeation of nanoparticles, mainly by changes of tissue structures or functions. The solid lipid nanoparticles (SLNs) were prepared by microfluidic method, considering the poor stability of both arginine modified cholesterol (Chol-Arg) and reduced coenzyme Q₁₀ that were used in prescription. These Q₁₀/NO-SLNs were then encapsulated in an anti-bacterial and glucose sensitive ε-polylysine (EPL) based hydrogel. The multiple bio-functions of Q₁₀/NO-SLN@EPL^gel system were investigated and proved thoroughly both in vitro and in vivo, including +677.8% wound healing rate, +670.0% nanoparticle permeation, +312.5% blood supply in wound area, and + 229.3% neuron density in wound sections. In conclusion, Q₁₀/NO-SLN@EPL^gel was proved to be an effective DFUs wound dressing, and promoting nerve regeneration should be considered vital in therapy of DFUs.

周围神经病变和微循环分布是糖尿病足溃疡（DFUs）的主要原因。基于一氧化氮（NO）的血管扩张和神经再生作用，本研究开发了一种多功能纳米颗粒-水凝胶治疗系统。为了抑制NO产生过氧亚硝酸盐阴离子（ONOO−）并导致细胞毒性的副作用，我们采用了生理性NO生成和抗氧化联合治疗的双重策略。这种原位NO生成也被证明加速了纳米颗粒的渗透，主要是通过改变组织结构或功能来实现的。针对处方中使用的精氨酸修饰胆固醇（cholr - arg）和还原性辅酶Q10稳定性较差的问题，采用微流控法制备了固体脂质纳米颗粒（SLNs）。然后将这些Q10/ no - sln包裹在抗菌和葡萄糖敏感的ε-聚赖氨酸（EPL）水凝胶中。Q10/NO-SLN@EPLgel体系具有+677.8%的创面愈合率、+670.0%的纳米颗粒通透性、+312.5%的创面血供、+ + 229.3%的创面神经元密度等多种生物功能。综上所述，Q10/NO-SLN@EPLgel是一种有效的DFUs创面敷料，促进神经再生在DFUs治疗中应被视为至关重要。

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引用次数: 0