Journal of Controlled Release最新文献_第3页

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

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

A hydrogen generator enhances immunogenic transarterial chemoembolization in hepatocellular carcinoma 氢发生器增强肝细胞癌经动脉化疗栓塞的免疫原性

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-06 DOI: 10.1016/j.jconrel.2026.114694

Lei Cao (1) , Li Ren (1) , Longlin Yin (1) , Ping Xie , Guangyin Qiu , Tao Lu , Xueqing Huang , Wenhao Li , Wencheng Wu , Kun Zhang , Shi Zhou

Conventional transarterial chemoembolization (TACE) regimens for hepatocellular carcinoma (HCC) are often compromised in efficacy due to hypoxia and acidosis within the tumor microenvironment (TME), frequently leading to unsatisfactory treatment outcomes and tumor recurrence. To overcome these limitations, this study introduces an innovative approach by incorporating a hydrogen generator (calcium hydride, CaH₂) into an epirubicin (EPI)–iodized oil embolization system. This design enables local hydrogen release to remodel the TME following TACE, thereby enhancing the combined chemo-immunotherapeutic antitumor response. Nano-CaH₂ particles, co-delivered locally via TACE, undergo hydrolysis to continuously release hydrogen gas (H₂) and calcium ions (Ca²⁺). This reaction disrupts mitochondrial function in cancer cells, reduces oxygen consumption, alleviates tumor hypoxia, and consequently counteracts chemoresistance. Simultaneously, EPI induces immunogenic cell death (ICD) in moribund tumor cells, activating the host's antitumor immune response. Additionally, the hydroxide ions generated from CaH₂ hydrolysis neutralize the acidic TME, alleviating immunosuppression and further amplifying the chemo-immunotherapeutic synergy mediated by TACE. This strategy presents a novel method to improve TACE efficacy and facilitate its integration with immunotherapy, demonstrating considerable potential for clinical translation.

传统的经动脉化疗栓塞（TACE）治疗肝细胞癌（HCC）方案往往由于肿瘤微环境（TME）缺氧和酸中毒而降低疗效，经常导致治疗效果不理想和肿瘤复发。为了克服这些限制，本研究引入了一种创新的方法，将氢发生器（氢化钙，CaH₂）纳入表阿霉素（EPI）碘化油栓塞系统。这种设计使局部氢释放能够在TACE后重塑TME，从而增强化疗-免疫治疗联合抗肿瘤反应。纳米cah₂颗粒通过TACE局部共递送，经过水解连续释放氢气（H₂）和钙离子（Ca2+）。这种反应破坏了癌细胞的线粒体功能，减少了氧气消耗，减轻了肿瘤缺氧，从而抵消了化疗耐药性。同时，EPI诱导垂死肿瘤细胞的免疫原性死亡（ICD），激活宿主的抗肿瘤免疫应答。此外，CaH 2水解产生的氢氧根离子中和了酸性TME，减轻了免疫抑制，进一步增强了TACE介导的化学-免疫治疗协同作用。该策略提供了一种提高TACE疗效并促进其与免疫治疗结合的新方法，显示出相当大的临床转化潜力。

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引用次数: 0

Self-amplifying pyroptosis nanoinducers enhance cancer immunotherapy through inflammasome priming and activation 自扩增焦亡纳米诱导剂通过炎性体的启动和激活增强癌症免疫治疗

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-05 DOI: 10.1016/j.jconrel.2026.114689

Wenyu Zhang , Changshun Huang , Chengzhilin Li , Xinyu Wang , Ying Qu , Wenlong Duan , Yingyu Hou , Yingchun Zhao , Qingbin He , Jianwei Jiao , Zhengwei Liu , Runxiao Zheng

Pyroptosis, a unique type of inflammatory programmed cell death, has recently been identified as a promising therapeutic target for activating the immune system. Nevertheless, the effectiveness of pyroptosis in tumor immunotherapy is impeded by critical factors such as the failure to address nuclear factor-κB (NF-κB) priming, insufficient inflammasome activation, and limited light and oxygen penetration. To confront these challenges, we constructed crystalline dendritic mesoporous gadolinium oxide (DM-Gd₂O₃ nanoparticles) loaded with a peroxyoxalate-based chemiluminescence system and encapsulated by calcium carbonate (CaCO₃) nanoparticles to form self-amplifying pyroptosis nanoinducers. Within the tumor microenvironment (TME), the release of pH-responsive calcium (Ca²⁺) and gadolinium ions (Gd³⁺) promotes the priming of NF-κB and disrupts lysosomal membrane phosphate groups, thereby inducing lysosomal rupture. Additionally, bis(3,4,6-trichloro-2-(pentyloxycarbonyl) phenyl) oxalate (CPPO) reacts with hydrogen peroxide (H₂O₂) to form a high-energy intermediate that emits light, exciting chlorin e6 (Ce6) to produce singlet oxygen. This process overcomes the limitations of light penetration and tumor hypoxia, synergizes with pyroptosis, and triggers a strong antitumor immune response in vitro and in vivo. This study introduces a novel approach to the design of self-amplifying pyroptosis nanoinducers for tumor immunotherapy.

焦亡是一种独特类型的炎性程序性细胞死亡，最近被确定为激活免疫系统的有希望的治疗靶点。然而，在肿瘤免疫治疗中，焦细胞凋亡的有效性受到一些关键因素的阻碍，如未能解决核因子-κB （NF-κB）的启动，炎症小体激活不足，以及光和氧穿透有限。为了应对这些挑战，我们构建了晶体树突状介孔氧化钆（DM-Gd2O3纳米颗粒），负载过氧草酸盐基化学发光系统，并被碳酸钙（CaCO3）纳米颗粒包裹，形成自扩增的焦亡纳米诱导剂。在肿瘤微环境（TME）内，ph响应性钙（Ca2+）和钆离子（Gd3+）的释放促进NF-κB的启动，破坏溶酶体膜磷酸基团，从而诱导溶酶体破裂。此外，二（3,4,6-三氯-2-（戊氧羰基）苯基）草酸盐（CPPO）与过氧化氢（H2O2）反应形成发光的高能中间体，激发氯e6 （Ce6）产生单线态氧。这一过程克服了光穿透和肿瘤缺氧的限制，与焦亡协同作用，在体外和体内引发了强烈的抗肿瘤免疫反应。本研究介绍了一种设计用于肿瘤免疫治疗的自扩增焦亡纳米诱导剂的新方法。

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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 : 2026-02-05 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