Journal of Controlled Release最新文献_第5页

ROS-amplifying nanoregulators: Precision thioredoxin reductase-targeted disruption of redox homeostasis overcomes tumor redox resistance ros扩增纳米调节剂：精确的硫氧还蛋白还原酶靶向破坏氧化还原稳态克服肿瘤氧化还原抵抗

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2025-12-26 DOI: 10.1016/j.jconrel.2025.114580

Lu Ga , Youtao Xin , Hongyu Liu , Qifeng Zhang , Wei Ning , Xinyan Wang , Yunjian Yu , Meihui Su , Hui Gao

Malignant tumors often develop resistance to oxidative stress therapies through metabolic reprogramming and reinforcing redox defense mechanisms. To overcome this challenge, we strategically targeted thioredoxin reductase (TrxR), a master regulator of cellular redox homeostasis. The hypothesis that TrxR disruption could impair the antioxidant capacity and restore the therapeutic sensitivity of tumors was evaluated. A tumor-selective nanoregulator, P-3@MIL-100@HA (PMH), was engineered, which combines a natural product-derived TrxR inhibitor (P-3) with an iron-based metal-organic framework (MIL-100), and features a hyaluronic acid (HA) coating to enable CD44-mediated delivery. The core component, P-3, was identified through systematic pharmacological screening and structural optimization as a promising TrxR inhibitor. PMH orchestrates triple redox disruption in resistant tumors: (1) effective TrxR inhibition by P-3 induces sustained hydrogen peroxide accumulation, amplifying oxidative stress; (2) GSH depletion via iron-mediated redox cycling cripples antioxidant defenses; and (3) Fenton-driven hydroxyl radical (·OH) generation further intensifies oxidative damage. Under the reductive tumor microenvironment, PMH exhibits stimuli-responsive release of P-3 and Fe²⁺, triggering dual apoptosis and pyroptosis. In gastric cancer models, PMH achieves superior therapeutic outcomes with minimal systemic toxicity. This study establishes a novel paradigm in oxidative stress-mediated antitumor therapy by successfully integrating TrxR inhibition with metal-based chemodynamic therapy (CDT) for the first time. Our work provides fundamental design principles for developing oxidative stress-amplifying nanotherapeutics and presents a clinically viable strategy against oxidative stress-resistant malignancies.

恶性肿瘤通常通过代谢重编程和强化氧化还原防御机制对氧化应激疗法产生抗性。为了克服这一挑战，我们战略性地瞄准了硫氧还蛋白还原酶（TrxR），它是细胞氧化还原稳态的主要调节因子。我们评估了TrxR破坏可能损害肿瘤抗氧化能力和恢复肿瘤治疗敏感性的假设。研究人员设计了一种肿瘤选择性纳米调节剂P-3@MIL-100@HA (PMH)，它将天然产物衍生的TrxR抑制剂（P-3）与铁基金属有机框架（MIL-100）结合在一起，并具有透明质酸（HA）涂层，使cd44介导的递送成为可能。通过系统的药理学筛选和结构优化，核心成分P-3被确定为一种有前景的TrxR抑制剂。PMH在耐药肿瘤中协调三重氧化还原破坏：(1)P-3有效抑制TrxR诱导持续过氧化氢积累，放大氧化应激；(2)通过铁介导的氧化还原循环消耗谷胱甘肽削弱抗氧化防御；(3) fenton驱动的羟基自由基（·OH）的产生进一步加剧了氧化损伤。在还原性肿瘤微环境下，PMH表现出P-3和Fe2+的刺激响应性释放，引发双凋亡和焦亡。在胃癌模型中，PMH以最小的全身毒性获得了优越的治疗效果。本研究首次成功地将TrxR抑制与金属基化学动力学治疗（CDT）结合起来，建立了氧化应激介导的抗肿瘤治疗的新范式。我们的工作为开发氧化应激放大纳米疗法提供了基本的设计原则，并提出了一种临床可行的抗氧化应激恶性肿瘤的策略。

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引用次数: 0

A fast-slow liposome based “orthodox-unexpected interplay” strategy for bacterial otitis media and associated hearing loss 基于快速-缓慢脂质体的“正统-意外相互作用”策略治疗细菌性中耳炎和相关听力损失

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2025-12-26 DOI: 10.1016/j.jconrel.2025.114579

Huaan Li , Letian Cao , Suling Huang , Peiwen Deng , Lifang Guo , Dingsheng Wen , Lu Wen , Gang Chen

Otitis media (OM), the most common infectious disease affecting the middle ear, is a major cause of hearing loss worldwide. It is primarily caused by bacteria such as Staphylococcus aureus (S. aureus), which invade the tympanum, form dense biofilms, and induce persistent inflammation. Conventional treatments rely on multiple doses of antibiotics, which often lead to drug resistance and ineffectiveness. Here, we introduce a fast-slow liposome platform (lip@Lys/NC) based on an “orthodox-unexpected interplay” principle, integrating bacteriolysis, quorum sensing inhibition, and anti-inflammation for effective biofilm disruption and inflammation reduction. Lip@Lys/NC consists of lysostaphin (Lys, for rapid bacteriolysis) and chitosan nanoparticles loaded with curcumin/tanshinone IIA (CUR/TSIIA, for sustained anti-biofilm and anti-inflammation effects), allowing immediate bacterial killing with prolonged therapeutic effect. In vitro studies demonstrate that lip@Lys/NC exhibits potent antibacterial activity against methicillin-resistant S. aureus (MRSA), disrupts biofilms, inhibits quorum sensing, and decreases pro-inflammatory factors. Notably, this synergistic effect does not induce drug resistance, unlike traditional antibiotics. In guinea pig models of S. aureus/MRSA-induced acute and chronic OM, lip@Lys/NC effectively reduces middle-ear inflammation and dismantles bacterial biofilms. Moreover, it protects cochlear hair cells, reduces inflammatory mediator infiltration into the inner ear, and prevents hearing loss, achieving an efficient “orthodox-unexpected interplay” strategy for OM treatments. This integrated system offers a promising non-antibiotic therapeutic approach for MRSA-associated OM, addressing both pathogen elimination and hearing preservation.

中耳炎（OM）是影响中耳最常见的感染性疾病，是全球听力损失的主要原因。它主要是由金黄色葡萄球菌（S. aureus）等细菌引起的，这些细菌侵入鼓室，形成致密的生物膜，并引起持续的炎症。传统的治疗方法依赖于多剂量的抗生素，这往往导致耐药性和无效。在这里，我们介绍了一种基于“正统-意想不到的相互作用”原理的快慢脂质体平台（lip@Lys/NC），将细菌溶解、群体感应抑制和抗炎症结合起来，有效地破坏生物膜和减少炎症。Lip@Lys/NC由溶葡萄球菌蛋白（lyys，用于快速细菌溶解）和壳聚糖纳米颗粒负载姜黄素/丹参酮IIA （CUR/TSIIA，用于持续的抗生物膜和抗炎症作用），可以立即杀死细菌并延长治疗效果。体外研究表明lip@Lys/NC对耐甲氧西林金黄色葡萄球菌（MRSA）具有强效抗菌活性，破坏生物膜，抑制群体感应，降低促炎因子。值得注意的是，与传统抗生素不同，这种协同效应不会引起耐药性。在金黄色葡萄球菌/ mrsa诱导的急性和慢性OM豚鼠模型中，lip@Lys/NC有效地减轻了中耳炎症并拆除了细菌生物膜。此外，它还可以保护耳蜗毛细胞，减少炎症介质向内耳的浸润，防止听力损失，实现OM治疗的有效“正统-意外相互作用”策略。这种综合系统为mrsa相关的OM提供了一种有前途的非抗生素治疗方法，同时解决了病原体消除和听力保护的问题。

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引用次数: 0

Absorbable microspheres sustaining epirubicin and TLR7 agonist release for transarterial chemo-immuno-embolization in liver tumor 可吸收微球维持表柔比星和TLR7激动剂释放用于肝肿瘤经动脉化疗-免疫栓塞

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2025-12-25 DOI: 10.1016/j.jconrel.2025.114576

Yan Wang , Jiakun Guo , Di Hu , Hujing Tan , Wanting Chen , Chao Deng , Xiaoli Zhu , Zhiyuan Zhong

Transarterial chemoembolization is a preferred medical intervention for unresectable advanced liver tumor patients. Its clinical efficacy is, nevertheless, undermined by poor control over drug release and immunosuppressed tumor microenvironment. In this work, we report on absorbable microspheres with excellent loading and controlled release of epirubicin and imiquimod, a toll-like receptor 7 agonist (EPI/IMQ@Asphere) for transarterial chemo-immuno-embolization (TACIE) in liver tumors. EPI/IMQ@Asphere while stable during storage steadily releases EPI in 4 weeks and IMQ in one week, continuously inducing immunogenic cell death and immune activation, respectively. Strikingly, one single injection of EPI/IMQ@Asphere into subcutaneous H22 murine liver tumor achieves complete regression in 5 out of 7 mice, all of which show complete resistance to tumor rechallenge, in line with robust and durable anti-cancer immune response. TACIE in orthotopic VX2 rabbit model reveals significant shrinkage of primary liver tumor and complete prevention of pulmonary metastasis, in which TACIE not only occludes tumor arteries and kills tumor cells but also amplifies tumoral CD8⁺/CD4⁺ T cell infiltration. Overall, TACIE based on EPI/IMQ@Asphere offers a highly appealing therapeutic strategy for advanced liver cancers.

经动脉化疗栓塞是晚期肝脏肿瘤患者不可切除的首选医疗干预手段。然而，由于药物释放控制不佳和免疫抑制肿瘤微环境，影响了其临床疗效。在这项工作中，我们报道了一种可吸收的微球，具有良好的负载和控释表柔比星和咪喹mod，一种toll样受体7激动剂（EPI/IMQ@Asphere），用于肝肿瘤的经动脉化疗-免疫栓塞（TACIE）。EPI/IMQ@Asphere在贮存期间稳定，在4周内稳定释放EPI，在1周内稳定释放IMQ，分别持续诱导免疫原性细胞死亡和免疫激活。引人注目的是，单次注射EPI/IMQ@Asphere到H22小鼠皮下肝脏肿瘤中，7只小鼠中有5只小鼠完全消退，所有小鼠都表现出对肿瘤再攻击的完全抵抗，这符合强大而持久的抗癌免疫反应。在原位VX2兔模型中，TACIE显示原发性肝肿瘤明显缩小，完全阻止肺转移，TACIE不仅阻塞肿瘤动脉，杀死肿瘤细胞，而且扩大肿瘤CD8+/CD4+ T细胞浸润。总体而言，基于EPI/IMQ@Asphere的TACIE为晚期肝癌提供了一种极具吸引力的治疗策略。

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引用次数: 0

3D printed sex-specific medicines: Excipient-mediated modulation boosts systemic drug exposure by more than three-fold in male rats 3D打印的性别特异性药物：在雄性大鼠中，赋形剂介导的调节使全身药物暴露增加了三倍以上

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2025-12-25 DOI: 10.1016/j.jconrel.2025.114577

Laxmi Prasanna Nandiraju , Patricija Januskaite , Siying Ruan , Yujia Qin , Iria Seoane-Viaño , Christine M. Madla , Keying Chen , Alvaro Goyanes , Yang Mai , Abdul W. Basit

Excipients, historically regarded as inert, are now being recognised for their ability to actively modulate biological targets, including intestinal efflux transporters such as P-glycoprotein (P-gp). We have previously shown that polyethylene glycol (PEG) excipients can selectively enhance the oral bioavailability of P-gp substrate drugs, particularly in males. This study examined how 3D printed formulations containing PEG 2000 influence the pharmacokinetics of silodosin, a P-gp substrate drug used for the treatment of benign prostatic hyperplasia in ageing men, using male and female Wistar rats. Initial concentration screening studies with aqueous solutions revealed that a 1 % w/v PEG 2000 concentration (corresponding to 5 mg) maximally increased silodosin systemic exposure by 36 % compared to the control in males, with no significant effect in females, confirming sex-specific pharmacokinetic modulation. To exploit this unique phenomenon, 5 mg of PEG 2000 was incorporated as a functional excipient into silodosin-loaded printlets (3D printed tablets) fabricated via direct powder extrusion. The printlets achieved complete drug release within 70 min, exhibiting highly similar dissolution profiles between test and control formulations (f₂ = 88.6). In vivo pharmacokinetic studies revealed that printlets containing PEG 2000 resulted in a 213 % increase in plasma exposure in males relative to the control, while no significant enhancement was observed in females. By integrating biological variables such as sex into formulation design and leveraging the promising potential of 3D printing, this study demonstrates for the first time how excipient functionality can be harnessed to develop sex-specific oral therapies and advance personalised oral drug delivery. These findings pave the way for the future clinical translation of sex- and excipient-driven therapeutic approaches.

赋形剂，历史上被认为是惰性的，现在被认为具有积极调节生物靶点的能力，包括肠外排转运蛋白，如p -糖蛋白（P-gp）。我们之前已经表明，聚乙二醇（PEG）赋形剂可以选择性地提高P-gp底物药物的口服生物利用度，特别是在男性中。本研究使用雄性和雌性Wistar大鼠研究了含有PEG 2000的3D打印配方如何影响西洛多辛的药代动力学，西洛多辛是一种用于治疗老年男性良性前列腺增生的P-gp底物药物。水溶液的初始浓度筛选研究显示，与对照组相比，1% w/v PEG 2000浓度（相当于5mg）最大限度地使男性西洛多辛全身暴露量增加36%，而对女性没有显著影响，证实了性别特异性药代动力学调节。为了利用这种独特的现象，5mg PEG 2000作为功能赋形剂加入到通过直接粉末挤压制造的硅酮负载的打印片（3D打印片剂）中。该小片在70分钟内完全释放药物，在试验制剂和对照制剂之间表现出高度相似的溶出曲线（f2 = 88.6）。体内药代动力学研究显示，与对照组相比，含有PEG 2000的小颗粒导致男性血浆暴露量增加213%，而在女性中没有明显增加。通过将性别等生物变量整合到配方设计中，并利用3D打印的巨大潜力，这项研究首次展示了如何利用赋形剂的功能来开发针对性别的口服疗法，并推进个性化口服给药。这些发现为未来临床转化性和赋形剂驱动的治疗方法铺平了道路。

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引用次数: 0

A subcutaneous implant that releases islatravir provides long-lasting protection against vaginal SHIV infection in macaques 皮下植入物释放islatravir，为猕猴阴道SHIV感染提供持久保护

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2025-12-25 DOI: 10.1016/j.jconrel.2025.114575

Michele B. Daly , Daniel Kim , Archana Krovi , Linying Li , Chasity A. Norton , Gregory J. Gatto , George Khalil , Marie Brake , Rachel Wier , James Mitchell , Ryan Johnson , Chuong Dinh , Tiancheng E. Edwards , Richard E. Halaand , Jonathan Lipscomb , Mackenzie L. Cottrell , Walid Heneine , J. Gerardo García-Lerma , Leah M. Johnson , Charles W. Dobard

Pre-exposure prophylaxis (PrEP) is crucial for curbing the global HIV epidemic. While daily oral drug regimens serve as the cornerstone of HIV PrEP, inconsistent adherence has highlighted the necessity for long-acting drug delivery systems to enhance user uptake and retention. In this study, we developed a ε-polycaprolactone (PCL) implant designed for sustained release of islatravir (ISL), a potent nucleoside reverse transcriptase translocation inhibitor (NRTTI) utilized in HIV treatment. In pig-tailed macaques, implantation of two ISL implants in the inner arms resulted in persistent ISL concentrations in plasma (median = 3.9 nM [range = 1.2–6.7]) and ISL-triphosphate (ISL-TP) levels in peripheral blood mononuclear cells (PBMCs) (median = 192.4 fmol/10⁶ PBMCs [range = 28.4–362.1]). After removal of one implant, median plasma ISL levels decreased approximately 2.7-fold (1.4 nM [range = 0.4–2.0]). These levels were similar to those observed in humans receiving daily oral ISL dosing of 0.25 mg/day, which is considered safe and effective (1.3 nM). Median ISL-TP levels also showed a decrease of about 2.5-fold (76.3 fmol/10⁶ PBMCs [range = 18.4–148.8]) but remained above the established PrEP protection threshold for up to 8 months. In efficacy studies with repeated vaginal challenges to SHIV_SF162P3, placebo controls were infected after a median of two SHIV exposures. After a cumulative total of 144 SHIV exposures, five of six macaques with ISL implants remained protected, resulting in an estimated efficacy of 96.8 % (CI = 74.9–99.6 %). The ISL implants were well-tolerated in macaques and showed no signs of ISL-induced lymphopenia over the 8-month dosing period. These findings support the clinical development of the PCL implant as a safe and effective long-acting drug delivery of ISL or other NRTTIs for long-acting HIV PrEP in women.

暴露前预防（PrEP）对于遏制全球艾滋病毒流行至关重要。虽然每日口服药物方案是艾滋病毒预防的基石，但依从性不一致突出了长效药物输送系统的必要性，以提高使用者的吸收和保留。在这项研究中，我们开发了一种ε-聚己内酯（PCL）植入物，设计用于缓释islatravir (ISL)， islatravir是一种有效的核苷逆转录酶易位抑制剂（NRTTI），用于治疗HIV。在长尾猕猴的内臂植入两个ISL植入物，导致血浆中ISL浓度持续升高（中值= 3.9 nM[范围= 1.2-6.7]），外周血单核细胞（PBMCs）中ISL-三磷酸（is - tp）水平持续升高（中值= 192.4 fmol/106 PBMCs[范围= 28.4-362.1]）。移除一个植入物后，血浆中位ISL水平下降约2.7倍（1.4 nM[范围= 0.4-2.0]）。这些水平与每天口服ISL剂量0.25 mg/天的人观察到的水平相似，被认为是安全有效的（1.3 nM）。中位is - tp水平也下降了约2.5倍（76.3 fmol/106 PBMCs[范围= 18.4-148.8]），但在长达8个月的时间里仍高于既定的PrEP保护阈值。在SHIVSF162P3反复阴道刺激的疗效研究中，安慰剂对照组在中位数两次SHIV暴露后感染。在累计144次SHIV暴露后，6只植入ISL的猕猴中有5只仍然受到保护，估计效力为96.8% （CI = 74.9 - 99.6%）。猕猴对ISL植入物的耐受性良好，在8个月的给药期间没有显示出ISL诱导的淋巴细胞减少的迹象。这些发现支持PCL植入物作为一种安全有效的长效药物递送ISL或其他nrtti用于女性长效HIV PrEP的临床发展。

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引用次数: 0

Pulmonary delivery of glycine-induced outer membrane vesicles as in situ vaccines for metastatic lung cancer 肺传递甘氨酸诱导的外膜囊泡作为转移性肺癌原位疫苗

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2025-12-25 DOI: 10.1016/j.jconrel.2025.114578

Wenwen Xu , Lu Wei , Xing Zhao , Yuhan Zhao , Tian Zhang , Jingwen Zhang , Siyuan Sun , Yingjie Ma , Lan Wu , Mingshi Yang , Dongmei Cun

Metastatic lung cancer's immunosuppressive tumor microenvironment (TME) remains a significant barrier to effective immunotherapy. While inhaled vaccination offers a promising strategy for local TME remodeling, potent and safe immunostimulants remain lacking. Bacterial outer membrane vesicles (OMVs) are emerging as promising nanoplatforms for cancer immunotherapy; however, their therapeutic efficacy, safety, and underlying mechanisms against metastatic lung cancer via lung mucosal immunity remain largely unexplored. To address this, we developed glycine-induced OMVs (Gomv) as a novel inhaled in situ vaccine, strategically leveraging preparation methodology to influence immunostimulatory function. This methodology-driven engineering significantly boosted immunogenicity, achieving a 7.28-fold increase in production yield alongside a substantially reduced lipopolysaccharide content (0.107 ± 0.002 ng/μg) and an enriched outer membrane protein profile (e.g., OmpA and OmpC) compared to other OMVs. Importantly, our results showed that Gomv targeted alveolar macrophages and promoted tumor phagocytosis and M1 polarization by activating the FPR1/2 and NF-κB pathways. The consequent release of tumor antigens functioned as an effective in situ vaccine, activating cytotoxic T cells and reprogramming the immunosuppressive TME through coordinated cytokine signaling (including IFN-α, IFN-γ, and Granzyme B). Critically, pulmonary delivery of Gomv achieved 83.17 % tumor suppression in metastatic lung cancer models with a favorable safety profile. Our study establishes a glycine-induced engineering strategy for developing efficient and safe inhalable vaccine platforms, providing a reference for bacterial vesicle-based platforms in pulmonary immunotherapy.

转移性肺癌的免疫抑制肿瘤微环境（TME）仍然是有效免疫治疗的重要障碍。虽然吸入疫苗为局部TME重塑提供了有希望的策略，但有效和安全的免疫刺激剂仍然缺乏。细菌外膜囊泡（OMVs）正在成为癌症免疫治疗的有前途的纳米平台；然而，它们的治疗效果、安全性以及通过肺粘膜免疫对抗转移性肺癌的潜在机制在很大程度上仍未被探索。为了解决这个问题，我们开发了甘氨酸诱导的omv （Gomv）作为一种新型吸入原位疫苗，策略性地利用制备方法来影响免疫刺激功能。这种方法驱动的工程显著提高了免疫原性，与其他omv相比，产量提高了7.28倍，脂多糖含量大幅降低（0.107 ± 0.002 ng/μg），外膜蛋白谱（如OmpA和OmpC）丰富。重要的是，我们的研究结果表明，Gomv靶向肺泡巨噬细胞，通过激活FPR1/2和NF-κB途径促进肿瘤吞噬和M1极化。随后肿瘤抗原的释放作为一种有效的原位疫苗，激活细胞毒性T细胞，并通过协调的细胞因子信号（包括IFN-α、IFN-γ和颗粒酶B）重新编程免疫抑制TME。至关重要的是，在转移性肺癌模型中，肺输送Gomv的肿瘤抑制率达到83.17% %，并且具有良好的安全性。本研究为开发高效安全的可吸入疫苗平台建立了甘氨酸诱导的工程策略，为基于细菌囊泡的肺部免疫治疗平台提供参考。

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引用次数: 0

Inhalable perfluorocarbon RNA nanocapsules overcome biological barriers to treat lung metastases 可吸入的全氟碳RNA纳米胶囊克服生物屏障治疗肺转移

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2025-12-23 DOI: 10.1016/j.jconrel.2025.114570

Kasturi Siddhanta , Neha Kumari , Aditya Sundar , Atefehsadat Monirvaghefi , Braeden R. Pinkerton , Ling Ding , C.J. Woslager , Marjina Akter Kalpana , Chinmay M. Jogdeo , Ashley R. Ravnholdt , Jill A. Poole , Joshua L. Santarpia , James E. Talmadge , David Oupický

Inhalation RNA therapy offers to transform treatment of pulmonary diseases, yet mucus trapping, immune clearance, and navigation of heterogeneous lung tissue architecture prevents RNA from reaching its target cells. Here, we advance our previously reported perfluorocarbon (PFC) emulsion polyplex platform by developing stably aerosolized PFC-based miRNA nanocapsules. These nanocapsules are stabilized by PAMD-C, which is a cholesterol-modified polymeric analog of the FDA-approved CXCR4 antagonist AMD3100 (plerixafor). The nanocapsules exhibit negligible immune clearance, minimal inflammatory response, and efficient mucus transport, while passively homing to lung epithelial and tumor cells. After a single aerosolized dose in orthotopic lung metastasis model, more than 60 % of cancer cells and most type II alveolar and bronchial epithelial cells internalized the nanocapsules, with observed pulmonary retention exceeding 48 h. The nanocapsule provokes negligible cytokine release, enabling repeated dosing. Treatment with therapeutic miR-34a mimic suppresses metastatic outgrowth, potentiates anti-tumor immunity, and doubles median survival relative to control paclitaxel chemotherapy. By combining unique PFC disposition features with RNA versatility, the delivery platform overcomes main biological barriers for inhalable RNA medicines and opens a translatable path for treating diverse pulmonary diseases.

吸入RNA疗法可以改变肺部疾病的治疗方式，但粘液捕获、免疫清除和异质性肺组织结构的导航阻止了RNA到达其靶细胞。在这里，我们通过开发稳定雾化的PFC基miRNA纳米胶囊来推进我们之前报道的全氟碳（PFC）乳液复合平台。这些纳米胶囊由PAMD-C稳定，PAMD-C是fda批准的CXCR4拮抗剂AMD3100 （plerixafor）的胆固醇修饰聚合物类似物。纳米胶囊表现出可忽略的免疫清除，最小的炎症反应和有效的粘液运输，同时被动地归巢到肺上皮和肿瘤细胞。在原位肺转移模型中，单次雾化剂量后，超过60% %的癌细胞和大多数II型肺泡和支气管上皮细胞内服纳米胶囊，观察到肺潴留超过48 h。纳米胶囊可引起可忽略不计的细胞因子释放，可重复给药。治疗性miR-34a模拟物治疗抑制转移性生长，增强抗肿瘤免疫，相对于对照紫杉醇化疗，中位生存期增加一倍。通过将独特的PFC配置特征与RNA多功能性相结合，该给药平台克服了可吸入RNA药物的主要生物学障碍，为治疗多种肺部疾病开辟了一条可翻译的途径。

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引用次数: 0

Non-invasive co-delivery of Axitinib and telmisartan via LDH-based nanocarriers for synergistic VEGF/Ang-2 inhibition in ocular neovascular diseases 阿西替尼和替米沙坦通过以ldh为基础的纳米载体无创共递送用于眼部新生血管疾病的协同VEGF/Ang-2抑制

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2025-12-23 DOI: 10.1016/j.jconrel.2025.114574

Meng Zhang , Yumei Wang , Jiayi Wang , Jiayi Zuo , Feng Jiang , Feng Cao

Neovascular ocular diseases are a leading cause of irreversible vision loss. Although intravitreal anti-VEGF therapy is the standard treatment, its invasive delivery and limited efficacy in some patients emphasize the need for non-invasive strategies targeting multiple angiogenic pathways. In this study, we developed a novel hybrid nanoplatform for the non-invasive co-delivery of axitinib (Axi) and telmisartan (Tel) to synergistically inhibit both VEGF and Ang-2 signaling pathways. Poorly soluble drugs were incorporated into layered double hydroxides (LDHs) via a micelle-assisted intercalation strategy and subsequently modified with hyaluronic acid (HA) conjugated to Gly-Val-Sar (GVS), a novel PepT1-targeted tripeptide. The Zn-containing LDH provided controlled drug release, and exhibited anti-inflammatory properties. HA modification prolonged ocular retention, and GVS enhanced transmembrane transport. The resulting Axi/Tel-D@LDH-HA-GVS nanocomposites demonstrated favorable physicochemical properties, efficient uptake by human conjunctival and retinal pigment epithelial cells, and potent inhibition of hypoxia-induced angiogenesis in vitro. In vivo, the formulations exhibited prolonged ocular retention, effective posterior tissue distribution, and good biosafety. In a diabetic retinopathy model, Axi/Tel-D@LDH-HA-GVS nanocomposites restored retinal structure and markedly reduced the expression of VEGF, Ang-2, TNF-α, and IL-6. Collectively, this study provides a promising non-invasive and synergistic strategy for targeted treatment of ocular neovascular diseases.

新生血管性眼部疾病是导致不可逆视力丧失的主要原因。尽管玻璃体内抗vegf治疗是标准的治疗方法，但其侵入性传递和对一些患者有限的疗效强调了针对多种血管生成途径的非侵入性策略的必要性。在这项研究中，我们开发了一种新的混合纳米平台，用于阿西替尼（Axi）和替米沙坦（Tel）的非侵入性共给药，以协同抑制VEGF和Ang-2信号通路。通过胶束辅助嵌入策略，将难溶性药物掺入层状双氢氧化物（LDHs）中，随后用透明质酸（HA）偶联Gly-Val-Sar （GVS）修饰，GVS是一种新型的pept1靶向三肽。含锌LDH具有控释药物和抗炎作用。透明质酸修饰延长了眼潴留，GVS增强了跨膜运输。结果表明，Axi/Tel-D@LDH-HA-GVS纳米复合材料具有良好的物理化学性质，可被人结膜和视网膜色素上皮细胞有效吸收，并能有效抑制体外缺氧诱导的血管生成。在体内，该制剂表现出持久的眼潴留，有效的后组织分布和良好的生物安全性。在糖尿病视网膜病变模型中，Axi/Tel-D@LDH-HA-GVS纳米复合材料可以恢复视网膜结构，并显著降低VEGF、Ang-2、TNF-α和IL-6的表达。总之，本研究为眼部新生血管疾病的靶向治疗提供了一种有前景的无创和协同策略。

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引用次数: 0

Structurally-defined non-cationic docosahexaenoic acid based siRNA-micelles for safe and effective combinatorial glioblastoma therapy 结构明确的非阳离子二十二碳六烯酸基sirna胶束用于安全有效的胶质母细胞瘤联合治疗

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2025-12-22 DOI: 10.1016/j.jconrel.2025.114568

Sen Xu , Mengyu Fan , Qimeng Ding , Yibin Wang , Muhammad Ismail , Weimin Ruan , Yan Zou , Dongya Zhang , Meng Zheng

RNA interference (RNAi) has emerged as a highly promising therapeutic strategy for glioblastoma (GBM), yet its clinical efficacy heavily relies on the success of delivery systems. Traditional vehicles, including cationic polymers, lipids, and inorganic nanoparticles, frequently encounter critical challenges such as cationic toxicity, poor blood-brain barrier (BBB) penetration, or poorly-defined structures that hinder their clinical translation. To overcome these challenges, we developed a novel, structurally-defined non-cationic siRNA-micelle system based on siRNA-docosahexaenoic acid (DHA) conjugates. These conjugates self-assemble into stable siRNA-micelles that exhibit prolonged blood circulation, enhanced cellular uptake, and efficient BBB penetration. Due to their non-cationic nature and the inherent safety profile of DHA, these siRNA-DHA₂₂ micelles exhibit exceptional biocompatibility, potentially minimizing carrier-based toxicity. By simultaneously targeting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGFA), the siRNA-micelles potently inhibited tumor progression and substantially extended survival in orthotopic GBM mouse models via dual-target modulation. This structurally-defined, non-cationic siRNA delivery platform represents a robust and clinically translatable strategy for GBM treatment, and holds considerable promise for the RNAi-based therapy of other neurological disorders.

RNA干扰（RNAi）已成为一种非常有前途的胶质母细胞瘤（GBM）治疗策略，但其临床疗效在很大程度上依赖于递送系统的成功。传统的载体，包括阳离子聚合物、脂质和无机纳米颗粒，经常遇到诸如阳离子毒性、血脑屏障（BBB）渗透性差或结构不明确等关键挑战，这些挑战阻碍了它们的临床转化。为了克服这些挑战，我们开发了一种基于sirna -二十二碳六烯酸（DHA）偶联物的新型、结构明确的非阳离子sirna -胶束体系。这些偶联物自组装成稳定的sirna胶束，表现出延长血液循环，增强细胞摄取和有效的血脑屏障渗透。由于它们的非阳离子性质和DHA固有的安全性，这些siRNA-DHA胶束表现出卓越的生物相容性，潜在地减少了载体毒性。通过同时靶向表皮生长因子受体（EGFR）和血管内皮生长因子（VEGFA）， sirna -胶束在原位GBM小鼠模型中通过双靶标调节有效地抑制肿瘤进展并显著延长生存期。这种结构明确的非阳离子siRNA传递平台代表了一种强大的、临床可翻译的GBM治疗策略，并对其他神经系统疾病的基于rna的治疗具有相当大的前景。

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引用次数: 0

Secreted protein acidic and rich in cysteine-guided biomimetic delivery of nano-antioxidants reverses muscle atrophy in a mouse model of sarcopenia 分泌的蛋白质酸性和丰富的半胱氨酸引导仿生递送纳米抗氧化剂逆转肌肉萎缩的小鼠模型中的肌肉减少

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2025-12-22 DOI: 10.1016/j.jconrel.2025.114567

Gai Kanazawa , Hitoshi Maeda , Kengo Yasuda , Isamu Noguchi , Ayano Nishinoiri , Kazuaki Taguchi , Shuhei Imoto , Kenji Tsukigawa , Keishi Yamasaki , Mina Sakuragi , Yu Ishima , Sadaharu Matsushita , Teruya Nakamura , Junji Saruwatari , Masaki Otagiri , Hiroshi Watanabe , Toru Maruyama

Sarcopenia is currently classified as an unmet medical need with an increasing incidence because of population aging. Excessive reactive oxygen species (ROS) production plays a critical role in the pathogenesis of muscle atrophy, a key feature of sarcopenia, whereas edaravone has been identified as a potent ROS scavenger in screening assays using C2C12 myocytes. In this study, we established an injured muscle-targeted drug delivery system (imDDS), which mimics the secreted protein acidic and rich in cysteine (SPARC)-mediated albumin uptake pathway, to deliver edaravone to damaged muscle tissue. SPARC on the cell surface facilitated the cellular uptake of human serum albumin (HSA) by forming disulfide bonds with the surface or intramolecular thiol groups of HSA. Endogenous albumin labeled with Evans blue accumulated in the injured muscle tissue of mice with sarcopenia, suggesting the potential of albumin to target damaged muscle tissue. Thiol-rich, edaravone-loaded HSA nanoparticles were internalized into hydrogen peroxide-injured myocytes in a SPARC-dependent manner, and edaravone was released into the cytosol in response to the acidic endosomal environment, resulting in a significant reduction of intracellular ROS levels. The nanoparticles also preferentially accumulated in SPARC-positive cells within the damaged muscle tissue of mice with sarcopenia and attenuated oxidative stress, thereby significantly restoring skeletal muscle mass and endurance. These findings suggest that edaravone-based, SPARC-guided biomimetic delivery represents a promising therapeutic strategy for sarcopenia and other muscle-related disorders.

骨骼肌减少症目前被归类为未满足的医疗需求，由于人口老龄化，发病率不断上升。过多的活性氧（ROS）的产生在肌肉萎缩的发病机制中起着关键作用，肌肉萎缩是肌肉减少症的一个关键特征，而在使用C2C12肌细胞的筛选试验中，依达拉曲已被确定为一种有效的ROS清除剂。在本研究中，我们建立了一种损伤肌肉靶向给药系统（imDDS），该系统模拟分泌蛋白酸性和富含半胱氨酸（SPARC）介导的白蛋白摄取途径，将依达拉奉递送到受损肌肉组织。细胞表面的SPARC通过与人血清白蛋白（HSA）的表面或分子内巯基形成二硫键，促进了人血清白蛋白的细胞摄取。内源性Evans蓝标记白蛋白在肌肉减少症小鼠的损伤肌肉组织中积累，提示白蛋白具有靶向损伤肌肉组织的潜力。富含硫醇、装载依达拉奉的HSA纳米颗粒以sparc依赖的方式内化到过氧化氢损伤的肌细胞中，依达拉奉被释放到细胞质中，以响应酸性内体环境，导致细胞内ROS水平显著降低。纳米颗粒也优先在肌肉减少症和氧化应激减弱的小鼠受损肌肉组织中的sparc阳性细胞中积累，从而显着恢复骨骼肌质量和耐力。这些发现表明，以依达拉奉为基础，sparc引导的仿生给药是治疗肌肉减少症和其他肌肉相关疾病的一种有希望的治疗策略。

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引用次数: 0