Journal of Controlled Release最新文献_第10页

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

Injectable Schiff base-engineered hydrogel for spatiotemporal liraglutide delivery orchestrates diabetic periodontitis regression via multimodal microenvironment reprogramming 用于利拉鲁肽时空递送的可注射希夫碱工程水凝胶通过多模态微环境重编程协调糖尿病牙周炎的回归

IF 10.8 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-05 DOI: 10.1016/j.jconrel.2026.114688

Jiamin Li, Rongrong Li, Yan Zhou, Shengping Zheng, Jingjing Xu, Jingli Zhu, Yunqing Pang, Jing Wang

The treatment of diabetic periodontitis is significantly challenged by a pathological microenvironment characterized by hyperglycemia, proinflammatory cytokine storm, and excessive reactive oxygen species (ROS), with current therapeutic strategies offering limited efficacy and susceptibility to antibiotic resistance. Although liraglutide (LIRA) possesses multifaceted therapeutic potential, including glycemic control, anti-inflammation, antioxidation, and osteoprotection, its systemic administration fails to achieve effective local concentrations within periodontal tissues. To address this, we engineered an injectable carboxymethyl chitosan-oxidized dextran hydrogel (LIRA@CMCS-OD) via dynamic Schiff base bonds for localized LIRA delivery. This hydrogel exhibited excellent injectability, tissue adhesion, biocompatibility, and pH-responsive drug release kinetics. In vitro studies demonstrated that LIRA@CMCS-OD inhibited Porphyromonas gingivalis growth, effectively scavenged intracellular ROS in human periodontal ligament cells (hPDLCs), and robustly promoted hPDLCs osteogenic differentiation. In a diabetic periodontitis rat model, local application of LIRA@CMCS-OD significantly ameliorated gingival inflammation and tooth mobility, enhanced alveolar bone regeneration, and demonstrated favorable biosafety. By enabling sustained local drug release and orchestrating a synergistic “antibacterial action-antioxidation- osteogenic protection” mechanism, this LIRA-loaded injectable hydrogel presents a potent and safe therapeutic strategy for diabetic periodontitis.

糖尿病牙周炎的治疗受到以高血糖、促炎细胞因子风暴和过多活性氧（ROS）为特征的病理微环境的显著挑战，目前的治疗策略疗效有限，易受抗生素耐药性的影响。尽管利拉鲁肽（liraglutide， LIRA）具有多方面的治疗潜力，包括血糖控制、抗炎症、抗氧化和骨保护，但其全身给药不能在牙周组织内达到有效的局部浓度。为了解决这个问题，我们设计了一种可注射的羧甲基壳聚糖氧化右旋糖酐水凝胶（LIRA@CMCS-OD），通过动态希夫碱键来局部递送LIRA。该水凝胶具有良好的可注射性、组织粘附性、生物相容性和ph反应性药物释放动力学。体外研究表明LIRA@CMCS-OD抑制牙龈卟啉单胞菌生长，有效清除人牙周韧带细胞（hPDLCs）细胞内ROS，有力促进hPDLCs成骨分化。在糖尿病牙周炎大鼠模型中，局部应用LIRA@CMCS-OD可显著改善牙龈炎症和牙齿活动，促进牙槽骨再生，并显示出良好的生物安全性。通过实现持续的局部药物释放和协调协同“抗菌-抗氧化-成骨保护”机制，这种装载lira的可注射水凝胶为糖尿病牙周炎提供了一种有效而安全的治疗策略。

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引用次数: 0

New-generation advanced Nano-PROTACs as potential therapeutic agents in cancer therapy 新一代先进的纳米protacs作为潜在的治疗药物在癌症治疗中

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-04 DOI: 10.1016/j.jconrel.2026.114673

Jingjuan Zhang , Yongzheng Li , Huiyuan Jin , Peizhen Yang , Huan Min , Jian Song , Yingqiu Qi

Proteolysis targeting chimeras (PROTACs) are catalytic degraders that eliminate pathogenic proteins via the ubiquitin-proteasome system (UPS). Building on this mechanism, nano-engineered PROTACs (Nano-PROTACs) integrate PROTACs with rationally designed nanomaterials to create an emerging therapeutic platform for cancer. This integrative approach preserves the core capability of PROTACs to precisely degrade pathogenic proteins through the UPS, and also confers multiple therapeutic advantages including enhanced tissue targeting, improved membrane permeability, and controlled drug release, thereby significantly improving cancer therapeutic efficacy while effectively reducing systemic toxicity. This review provides a comprehensive overview of recent advances in Nano-PROTACs for cancer therapy, with a particular focus on the design strategies enabled by nanomaterial-based delivery systems, along with the applications in monotherapy and synergistic therapies. In addition, the therapeutic advantages and existing challenges of Nano-PROTACs are critically discussed, while delineating their potential future clinical applications, providing critical insights to the understanding of this emerging technology and offering novel perspectives for future development of precision therapeutics.

蛋白水解靶向嵌合体（PROTACs）是通过泛素-蛋白酶体系统（UPS）消除致病性蛋白的催化降解剂。基于这一机制，纳米工程PROTACs （Nano-PROTACs）将PROTACs与合理设计的纳米材料相结合，创造了一个新兴的癌症治疗平台。这种综合方法既保留了PROTACs通过泛素-蛋白酶体系统精确降解致病蛋白的核心能力，又具有增强组织靶向性、改善膜通透性、控制药物释放等多种治疗优势，从而在有效降低全身毒性的同时显著提高肿瘤治疗效果。本文综述了纳米protacs用于癌症治疗的最新进展，特别关注基于纳米材料的递送系统的设计策略，以及在单药治疗和协同治疗中的应用。此外，本文还对纳米protacs的治疗优势和存在的挑战进行了批判性的讨论，同时描述了其潜在的未来临床应用，为理解这一新兴技术提供了关键的见解，并为未来精确治疗的发展提供了新的视角。

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引用次数: 0

ApoE-directed CpG nano-immunoadjuvant ameliorates Alzheimer's-like pathology in mice apoe导向的CpG纳米免疫佐剂改善小鼠阿尔茨海默病样病理。

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-04 DOI: 10.1016/j.jconrel.2026.114687

Xin Huang , Yan-Yun Sun , Yi-Ren Qin , Hong Chen , Ting-Ting Pan , Song-Song Zhao , Qian Cai , Xiao-Shuo Zhang , Xiao-Dong Nie , Lei Feng , Hua Hu , Yong Tang , Pei-Zhuo Zhang , Zhi-Yuan Zhong , Jie Li , Li Lu , Feng-Hua Meng , Quan-Hong Ma

Toll-like receptor 9 (TLR9), expressed in both microglia and neurons of the CNS, represents a promising therapeutic target for Alzheimer's disease (AD). While either microglial or neuronal TLR9 activation exerts neuroprotective effects that ameliorate AD pathology and preserve cognitive function, CpG oligodeoxynucleotides (ODNs), the synthetic agonists, cannot cross the blood-brain barrier (BBB). To overcome this, we developed tNCpG, an apolipoprotein E (ApoE)-functionalized polymersome nanocarrier for brain-targeted delivery of CpG ODNs. APP/PS1 transgenic mice, which overexpress human mutant APP/PS1 and are widely used in AD mouse models for preclinical studies, were administered tNCpG intravenously biweekly for 3 months, starting at 4 months of age. tNCpG achieved efficient brain delivery while specifically targeting microglia and neurons. tNCpG treatment enhanced microglial recruitment to and phagocytosis of Aβ plaques, suppressed Aβ production while promoting its degradation, and improved BBB integrity and Aβ efflux. Collectively, these effects significantly reduced cerebral Aβ burden, neuroinflammation, and neurodegeneration, leading to the rescue of cognitive deficits. Our study establishes targeted TLR9 activation via tNCpG as a disease-modifying therapeutic strategy for AD.

toll样受体9 （TLR9）在中枢神经系统的小胶质细胞和神经元中均有表达，是阿尔茨海默病（AD）的一个有希望的治疗靶点。虽然小胶质细胞或神经元的TLR9激活可以发挥神经保护作用，改善AD病理和保持认知功能，但CpG寡脱氧核苷酸（odn），合成激动剂，不能穿过血脑屏障（BBB）。为了克服这个问题，我们开发了tNCpG，一种载脂蛋白E （ApoE）功能化的聚合物纳米载体，用于脑靶向递送CpG ODNs。APP/PS1转基因小鼠过度表达人类突变体APP/PS1，广泛用于临床前研究的AD小鼠模型，从4 月龄开始，每两周静脉注射tNCpG，持续3 个月。tNCpG在特异性靶向小胶质细胞和神经元的同时实现了高效的脑递送。tNCpG治疗增强了小胶质细胞对Aβ斑块的募集和吞噬，抑制了Aβ的产生，同时促进了其降解，改善了血脑屏障的完整性和Aβ的外排。总的来说，这些作用显著减少了脑Aβ负荷、神经炎症和神经变性，从而挽救了认知缺陷。我们的研究建立了通过tNCpG靶向激活TLR9作为AD的一种疾病改善治疗策略。

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引用次数: 0

Translational m-PBPK Modeling reveals active transcytosis as the pivotal mechanism for nanoparticle tumor delivery: Implications for dose optimization 翻译m-PBPK模型揭示了活跃的胞吞作用是纳米颗粒肿瘤递送的关键机制：对剂量优化的影响

IF 11.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2026-02-03 DOI: 10.1016/j.jconrel.2026.114684

Jinwei Zhu , Hui Lin , Kejie Wang , Sasa Zhang , Hua He , Kun Hao

The long-held assumption that passive diffusion governs nanomedicine entry into the tumors has been increasingly challenged, with accumulating evidence implicating transcytosis as an important route for nanoparticle transport across the tumor endothelium. However, quantitative comparisons of their relative contributions remain scarce. To address this gap, this study developed a minimal physiologically based pharmacokinetic (m-PBPK) model that integrates in vitro cellular kinetic data to quantitatively describe to tumor delivery of nanoparticles and to assess the relative contributions of diffusion- and transcytosis-mediated transport within a model-based context. The framework was evaluated using PEGylated gold nanoparticles (AuNPs) spanning a range of particle sizes and incorporated empirical size-parameter relationships to enable in vitro-in vivo translational analysis. Model simulations suggested that transcytosis-mediated processes account for the majority of tumor AuNP accumulation under the modeled physiological conditions (99.0 %, 95 % CI: 94.7 %–99.8 %), whereas passive diffusion contributed a smaller fraction under most conditions examined. Dose-dependent analysis further indicated a capacity-limited tumor accumulation behavior, with a threshold around 18 mg, beyond which increasing the dose to 100 mg resulted in only a modest (∼15 %) increase in tumor accumulation. Sensitivity analyses indicated that systemic exposure and endothelial intracellular trafficking behavior are key determinants influencing tumor delivery, whereas enhanced intracellular sequestration consistently reduced tumor accumulation across dose levels. Overall, the proposed m-PBPK framework provides mechanistically interpretable, proof-of-concept insights into nanoparticle tumor delivery, supporting quantitative assessment of transcytosis efficiency and dose-dependent accumulation behavior for hypothesis generation in nanomedicine development.

长期以来，纳米药物通过被动扩散进入肿瘤的假设受到越来越多的挑战，越来越多的证据表明，胞吞作用是纳米颗粒通过肿瘤内皮运输的重要途径。然而，对它们的相对贡献的定量比较仍然很少。为了解决这一空白，本研究开发了一个基于生理的最小药代动力学（m-PBPK）模型，该模型整合了体外细胞动力学数据，以定量描述纳米颗粒的肿瘤递送，并评估扩散和胞吞介导的运输在基于模型的背景下的相对贡献。使用聚乙二醇化金纳米颗粒（AuNPs）对该框架进行评估，该框架跨越了一系列粒径，并结合了经验尺寸-参数关系，以实现体内外翻译分析。模型模拟表明，在模拟的生理条件下，胞吞介导的过程占肿瘤AuNP积累的大部分（99.0%,95% CI: 94.7% - 99.8%），而在大多数条件下，被动扩散贡献的比例较小。剂量依赖性分析进一步表明了一种容量有限的肿瘤积累行为，其阈值约为18 mg，超过该阈值，将剂量增加到100 mg仅导致肿瘤积累适度增加（~ 15%）。敏感性分析表明，全身暴露和内皮细胞内运输行为是影响肿瘤递送的关键决定因素，而增强的细胞内隔离在不同剂量水平上一致地减少了肿瘤积累。总的来说，所提出的m-PBPK框架为纳米颗粒肿瘤传递提供了机制上可解释的概念验证，支持对细胞吞噬效率和剂量依赖性积累行为的定量评估，为纳米药物开发中的假设生成提供了支持。

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引用次数: 0