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Urinary microenvironment-degradable nanocapsules for traceable therapy of diabetic nephropathy 尿微环境可降解纳米胶囊用于糖尿病肾病的可追溯治疗
IF 10.2 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2026-04-01 Epub Date: 2026-01-22 DOI: 10.1016/j.mtbio.2026.102833
Ru Feng , Tao Yue , Xuhui Zhao , Jie Dong , Jin Zhang , Xiaoyang Peng , Huifang Zhao , Jinghua Sun , Ruiping Zhang
Diabetic nephropathy (DN) is a serious complication of diabetes and a leading cause of end-stage renal disease. Current treatments using anti-inflammatory, antioxidant, and antifibrotic drugs are limited by rapid systemic clearance and poor renal retention. Here, we developed a urine-microenvironment responsive nanocapsule, MNP-THA@MnCaP, composed of a MnCaP nanoshell co-loaded with functionalized melanin (MNP) nanoparticles and thalidomide (THA) for synergistic therapy of DN. The nanocapsules preferentially accumulate in the kidneys via passive targeting and degrade under acidic urinary conditions, enabling controlled release of therapeutic agents. In vitro, MNP-THA@MnCaP alleviated oxidative stress, suppressed epithelial-mesenchymal transition, and reduced apoptosis in renal tubular cells. In vivo, the formulation targeted DN kidneys, attenuated oxidative injury, inflammation, and fibrosis, and restored renal function. Moreover, the released Mn2+ allowed T1-weighted magnetic resonance imaging, while MNP supported photoacoustic imaging, facilitating real-time tracking of the treatment process. With excellent biocompatibility and biodegradability, MNP-THA@MnCaP represents a promising theranostic platform with strong translational potential for DN treatment.
糖尿病肾病(DN)是糖尿病的严重并发症和终末期肾脏疾病的主要原因。目前使用抗炎、抗氧化和抗纤维化药物的治疗受到快速全身清除和肾潴留不良的限制。在这里,我们开发了一种尿微环境响应纳米胶囊MNP-THA@MnCaP,由MnCaP纳米壳与功能化黑色素(MNP)纳米颗粒和沙利度胺(THA)共同负载,用于协同治疗DN。纳米胶囊通过被动靶向在肾脏中优先积累,并在酸性尿液条件下降解,从而控制治疗剂的释放。在体外,MNP-THA@MnCaP可减轻肾小管细胞氧化应激,抑制上皮-间质转化,减少细胞凋亡。在体内,该制剂靶向DN肾脏,减轻氧化损伤、炎症和纤维化,恢复肾功能。此外,释放的Mn2+允许进行t1加权磁共振成像,而MNP支持光声成像,便于实时跟踪处理过程。MNP-THA@MnCaP具有良好的生物相容性和可生物降解性,是一个很有前途的治疗平台,具有很强的DN治疗转化潜力。
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引用次数: 0
Ultrasound-responsive CPS piezoelectric hydrogel synergistically repairs annulus fibrosus defects through immune reprogramming and cell recruitment 超声响应CPS压电水凝胶通过免疫重编程和细胞募集协同修复纤维环缺损
IF 10.2 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2026-04-01 Epub Date: 2026-01-19 DOI: 10.1016/j.mtbio.2026.102825
Huajun Pan , Chengzhi Liang , Shuihua Ding , Peichuan Xu , Changxiong Cai , Chongzhi Pan , Wei Xiong , Haiyan Li , Xinxin Miao , Xigao Cheng
As a globally prevalent cause of disability, lumbar disc herniation has structural disruption of the annulus fibrosus (AF) as its pathological core. To address three critical bottlenecks in AF repair—microenvironmental imbalance (excessive inflammation/oxidative stress), inadequate cellular regeneration (low cell density), and mechanical instability—this study developed an ultrasound-responsive piezoelectric hydrogel scaffold (CPS gel) composed of cerium dioxide, poly-L-lactic acid fibers, and sodium alginate. The core mechanisms include: 1) Immune Reprogramming: Ceria nanoparticles exert dual superoxide dismutase/catalase-mimetic catalytic activity to scavenge reactive oxygen species, inhibit the NF-κB signaling pathway, downregulate IKKα/IκBα phosphorylation, and thereby drive macrophage polarization toward the M2 phenotype; 2) Directed Cellular Regeneration: Ultrasound-activated piezoelectric effects from PLLA fibers facilitate cell migration and proliferation via the ITGβ1/PI3K/AKT/ERK pathway, promoting collagen secretion; 3) Mechanical Reconstruction: The sodium alginate 'egg-box' network provides physiologically matched compressive modulus, and in vivo experiments confirm the restoration of intervertebral disc compressive stiffness. Employing a triple synergistic strategy—immunomodulation, cell recruitment, and mechanical restoration—this study proposes a promising solution for structural regeneration of the annulus fibrosus.
腰椎间盘突出症是一种全球普遍存在的致残原因,其病理核心是纤维环的结构性破坏。为了解决心房纤颤修复的三个关键瓶颈——微环境失衡(过度炎症/氧化应激)、细胞再生不足(细胞密度低)和机械不稳定,本研究开发了一种由二氧化铈、聚l -乳酸纤维和海藻酸钠组成的超声响应压电水凝胶支架(CPS凝胶)。其核心机制包括:1)免疫重编程:纳米二氧化锆发挥双超氧化物歧化酶/模拟过氧化氢酶的催化活性,清除活性氧,抑制NF-κB信号通路,下调IKKα/ i -κB α磷酸化,从而驱动巨噬细胞向M2表型极化;2)定向细胞再生:超声激活PLLA纤维的压电效应通过itg - β1/PI3K/AKT/ERK通路促进细胞迁移和增殖,促进胶原分泌;3)机械重建:海藻酸钠“蛋盒”网络提供生理匹配的压缩模量,体内实验证实了椎间盘压缩刚度的恢复。采用三重协同策略-免疫调节,细胞募集和机械修复-本研究提出了一种有希望的纤维环结构再生解决方案。
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引用次数: 0
Shooting two hawks with one arrow: manganese-doped mesoporous carriers coordinate STING activation and enhanced mRNA translation for in situ cytokine delivery 一箭双雕:锰掺杂介孔载体协调STING激活和增强mRNA翻译,以实现细胞因子的原位传递
IF 10.2 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2026-04-01 Epub Date: 2026-01-12 DOI: 10.1016/j.mtbio.2026.102802
Yakai Yan , Liuyi Chen , Yue Wu , Xinrong Qu , Xiang Ma , Xing Sun , Guangya Xiang , Yao Lu
Cytokine mRNAs, such as IL-12, hold significant promise for anti-tumor therapy. However, their effective localized delivery and the prevention of off-target translation remain challenging. To address these challenges, we synthesized manganese-doped organic mesoporous carriers for mRNA delivery (PMSMns). The Mn doping in PMSMns not only boosted mRNA expression but also enhanced the immune response. Mechanistically, we verified that PMSMns enhance the translation process by relieving glyceraldehyde 3-phosphate dehydrogenase-mediated translational repression and upregulating the level of phosphorylated ribosomal protein S6. Meanwhile, the immune response was enhanced by activating the stimulator of interferon genes (STING) pathway. Furthermore, effective local delivery of mRNA only in tumors without off-target expression in other organs was also achieved. The PMSMns-IL-12/15-mRNA group exhibited the highest levels of IFN-γ, the greatest infiltration of CD8+ T cells, and the most robust recruitment of NK cells, achieving a potent synergistic antitumor effect. Overall, PMSMns provide a dual benefit: boosting mRNA translation and activating the STING pathway, making them ideally suited for cytokine mRNA-based tumor therapy.
细胞因子mrna,如IL-12,在抗肿瘤治疗中具有重要的前景。然而,它们的有效本地化传递和防止脱靶翻译仍然是一个挑战。为了解决这些挑战,我们合成了锰掺杂的有机介孔mRNA递送载体(PMSMns)。在PMSMns中掺杂Mn不仅可以提高mRNA的表达,还可以增强免疫应答。在机制上,我们证实PMSMns通过缓解甘油醛3-磷酸脱氢酶介导的翻译抑制和上调磷酸化核糖体蛋白S6的水平来增强翻译过程。同时,激活干扰素基因刺激因子(STING)通路可增强免疫应答。此外,还实现了mRNA仅在肿瘤中有效的局部递送,而在其他器官中没有脱靶表达。PMSMns-IL-12/15-mRNA组表现出最高水平的IFN-γ,最大的CD8+ T细胞浸润和最强大的NK细胞募集,实现了有效的协同抗肿瘤作用。总的来说,PMSMns提供了双重好处:促进mRNA翻译和激活STING途径,使它们非常适合细胞因子mRNA为基础的肿瘤治疗。
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引用次数: 0
Injectable chitosan-based hydrogel via in situ gelation modulates the inflammatory microenvironment and facilitates minimally invasive repair of peripheral nerve injury 可注射壳聚糖水凝胶通过原位凝胶调节炎症微环境,促进周围神经损伤的微创修复
IF 10.2 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2026-04-01 Epub Date: 2026-01-16 DOI: 10.1016/j.mtbio.2026.102814
Yunhao Zhai , Xiangheng Guan , Caorui Lu , Ruixuan Sun , Yun Qian , Yi Li , Kaihang Zhang , Xu Wang , Linbin Xu , Xinghao Yin , Shang Guo , Jinglei Wu , Cunyi Fan
Non-transecting peripheral nerve injuries require effective inflammation control, support of axon regeneration, and strategies that minimize additional surgical trauma. Injectable hydrogels are attractive carriers for local therapy, and chitosan is a widely used biocompatible matrix; however, conventional chitosan systems often depend on acidic dissolution and crosslinking or cytotoxic crosslinkers, which may aggravate nerve injury and hinder clinical translation. Here, we develop an injectable chitosan-based hydrogel (IBU-CS-GP) in which ibuprofen is complexed with chitosan for solubility range expansion toward near-neutral pH, thereby permitting genipin-mediated crosslinking under near-physiological pH and resolving the mismatch between chitosan solubility and the optimal pH for genipin. The resulting hydrogel forms a stable depot after perineural injection, enabling minimally invasive in situ gelation and localized drug delivery. We characterize its physicochemical properties, ibuprofen release profile, and biosafety, and evaluate its immunomodulatory and pro-regenerative effects in vitro and in a rat sciatic nerve crush model. In vitro, the IBU-CS-GP hydrogel suppresses macrophage inflammatory activation and reduces pro-inflammatory mediator production, thereby promoting a repair-supportive phenotype; in parallel, it indirectly enhances endothelial and stromal cell activities involved in angiogenesis and matrix remodeling. In vivo, perineural injection results in sustained ibuprofen release, accompanied by accelerated recovery of gait and nerve conduction, better preservation of gastrocnemius muscle mass and architecture, and more organized axon regeneration. These data suggest that the IBU-CS-GP hydrogel is a promising minimally invasive local therapy for non-transecting peripheral nerve injuries, as it enables near-neutral-pH in situ gelation and modulates the post-injury microenvironment.
非横断性周围神经损伤需要有效的炎症控制,支持轴突再生,以及最小化额外手术创伤的策略。注射水凝胶是局部治疗的重要载体,壳聚糖是一种广泛应用的生物相容性基质;然而,传统的壳聚糖系统往往依赖于酸性溶解和交联或细胞毒性交联剂,这可能会加重神经损伤并阻碍临床转译。在这里,我们开发了一种可注射的壳聚糖基水凝胶(IBU-CS-GP),其中布洛芬与壳聚糖络合,使其溶解度范围向接近中性的pH扩展,从而允许在接近生理pH下进行壳聚糖介导的交联,并解决壳聚糖溶解度与最佳pH之间的不匹配。所得到的水凝胶在神经周围注射后形成稳定的储库,实现微创原位凝胶化和局部给药。我们对其理化性质、布洛芬释放谱和生物安全性进行了表征,并在体外和大鼠坐骨神经挤压模型中评估了其免疫调节和促进再生的作用。在体外,IBU-CS-GP水凝胶抑制巨噬细胞炎症激活,减少促炎介质的产生,从而促进修复支持表型;同时,它间接增强内皮细胞和基质细胞在血管生成和基质重塑中的活性。在体内,神经周围注射导致布洛芬持续释放,同时加速步态和神经传导的恢复,更好地保存腓肠肌质量和结构,更有组织的轴突再生。这些数据表明,IBU-CS-GP水凝胶是一种很有前景的微创局部治疗非横断性周围神经损伤的方法,因为它可以实现接近中性ph的原位凝胶化,并调节损伤后的微环境。
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引用次数: 0
Copper-enriched zinc peroxides induced cuproptosis through concurrent metabolic and oxidative dysregulation for boosting immunotherapy in colorectal cancer 富铜过氧化物锌通过同步代谢和氧化失调诱导铜沉降,促进结直肠癌的免疫治疗
IF 10.2 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2026-04-01 Epub Date: 2026-01-19 DOI: 10.1016/j.mtbio.2026.102830
Shaopeng Zhang , Shaokang Yang , Mingqi Li , Hao Zhang , Yue Cao , Shiqi Bai , Wei Li , Bin Wang , Donghao Qu , Ziqian Wang , Wanying Li , Yanxu Sun , Daguang Wang , Yinghui Wang , Hongjie Zhang
Despite the immunotherapy has achieved the progress for advanced colorectal cancer, the unsatisfactory treatment effect remains a challenge due to the deficient immune response. In this work, we constructed a tumor microenvironments (TME)-responsive biodegradable cuproptosis inducer (ZnO2-Cu@HA, ZCH) through cation-exchange method for amplifying the immune response. Compared to free copper ions, ZCH cloud achieve the controllable release of Cu2+ in tumor site, trggering efficient cuproptosis but reducing the side effect of normal tissues. Furthermore, the released Zn2+ could also inhibit intracellular glycolysis and ATP generation, then block the ATP7B to reduce the efflux of copper ions. Meanwhile, ZCH broke intracellular redox homeostasis via the release of exogenous H2O2, Cu+-mediated Fenton-like reaction and Zn2+-induced endogenous mitoROS, amplifying the cuproptosis to inducing immunogenic cell death (ICD) triggered for highly efficient immunotherapy of colorectal cancer. These findings demonstrated that it is a promising strategy of inducing efficient cuproptosis by the synergistic effect of accumulation of copper ions, inhibiting glycolysis and down-regulation GSH for efficient immunotherapy of colorectal cancer.
尽管免疫疗法治疗晚期结直肠癌取得了进展,但由于免疫应答不足,治疗效果不理想仍然是一个挑战。本研究通过阳离子交换法构建了肿瘤微环境(TME)反应的可生物降解铜化诱导剂(ZnO2-Cu@HA, ZCH),以增强免疫应答。与游离铜离子相比,ZCH云在肿瘤部位实现了Cu2+的可控释放,触发高效铜沉淀,同时减少了对正常组织的副作用。此外,释放的Zn2+还可以抑制细胞内糖酵解和ATP的生成,从而阻断ATP7B,减少铜离子的外排。同时,ZCH通过外源性H2O2的释放、Cu+介导的Fenton-like反应和Zn2+诱导的内源性mitoROS,打破细胞内氧化还原稳态,放大cuprotosis,诱导免疫原性细胞死亡(immunogenic cell death, ICD),从而引发结直肠癌的高效免疫治疗。这些发现表明,通过铜离子积累、抑制糖酵解和下调谷胱甘肽的协同作用,诱导有效的铜还原是一种有效的结肠直肠癌免疫治疗策略。
{"title":"Copper-enriched zinc peroxides induced cuproptosis through concurrent metabolic and oxidative dysregulation for boosting immunotherapy in colorectal cancer","authors":"Shaopeng Zhang ,&nbsp;Shaokang Yang ,&nbsp;Mingqi Li ,&nbsp;Hao Zhang ,&nbsp;Yue Cao ,&nbsp;Shiqi Bai ,&nbsp;Wei Li ,&nbsp;Bin Wang ,&nbsp;Donghao Qu ,&nbsp;Ziqian Wang ,&nbsp;Wanying Li ,&nbsp;Yanxu Sun ,&nbsp;Daguang Wang ,&nbsp;Yinghui Wang ,&nbsp;Hongjie Zhang","doi":"10.1016/j.mtbio.2026.102830","DOIUrl":"10.1016/j.mtbio.2026.102830","url":null,"abstract":"<div><div>Despite the immunotherapy has achieved the progress for advanced colorectal cancer, the unsatisfactory treatment effect remains a challenge due to the deficient immune response. In this work, we constructed a tumor microenvironments (TME)-responsive biodegradable cuproptosis inducer (ZnO<sub>2</sub>-Cu@HA, ZCH) through cation-exchange method for amplifying the immune response. Compared to free copper ions, ZCH cloud achieve the controllable release of Cu<sup>2+</sup> in tumor site, trggering efficient cuproptosis but reducing the side effect of normal tissues. Furthermore, the released Zn<sup>2+</sup> could also inhibit intracellular glycolysis and ATP generation, then block the ATP7B to reduce the efflux of copper ions. Meanwhile, ZCH broke intracellular redox homeostasis via the release of exogenous H<sub>2</sub>O<sub>2</sub>, Cu<sup>+</sup>-mediated Fenton-like reaction and Zn<sup>2+</sup>-induced endogenous mitoROS, amplifying the cuproptosis to inducing immunogenic cell death (ICD) triggered for highly efficient immunotherapy of colorectal cancer. These findings demonstrated that it is a promising strategy of inducing efficient cuproptosis by the synergistic effect of accumulation of copper ions, inhibiting glycolysis and down-regulation GSH for efficient immunotherapy of colorectal cancer.</div></div>","PeriodicalId":18310,"journal":{"name":"Materials Today Bio","volume":"37 ","pages":"Article 102830"},"PeriodicalIF":10.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Smart nebulized ROS-responsive hydrogel microspheres loaded with UC-MSCs-derived exosomes for the treatment of acute lung injury 装载uc - msc衍生外泌体的智能雾化ros反应水凝胶微球用于治疗急性肺损伤
IF 10.2 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2026-04-01 Epub Date: 2026-02-04 DOI: 10.1016/j.mtbio.2026.102868
Chang Liu , Guoan Xiang , Yan Cao , Jianqiao Xu , Xiaoxiang Hu , Shoulong Deng , Kun Xiao , Lixin Xie
Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) are rapidly progressing, highly fatal clinical syndromes characterized by acute and progressive hypoxic respiratory failure. These conditions result in significant morbidity and mortality, yet no specific treatments are currently available, with management relying largely on symptomatic and supportive care. The pathogenesis of ALI/ARDS is closely linked to the excessive production of reactive oxygen species (ROS) and an uncontrolled inflammatory response, which collectively drive disease progression and tissue damage. To address this, we have developed a novel ROS-responsive hydrogel microsphere encapsulating human umbilical mesenchymal stem cell-derived exosomes, designated Exo@TK@CaAlg hydrogel microspheres. The design incorporates thioketal bonds, endowing the microspheres with both effective ROS-scavenging ability and specific responsiveness to oxidative stress. Exo@TK@CaAlg microspheres exhibit a small particle size and excellent biocompatibility in vitro and in vivo. Their potent ROS scavenging capacity positions them as a promising therapeutic approach for alleviating ALI. In preclinical studies, these microspheres have been successfully delivered via nebulization to the lungs of ALI mice, where they play a critical role in mitigating oxidative stress and inflammation. The treatment enhances pulmonary capillary barrier integrity, reduces protein exudation, restores mitochondrial function, and promotes the transition of macrophages from a pro-inflammatory to an anti-inflammatory phenotype. These collective findings highlight the potential of Exo@TK@CaAlg hydrogel microspheres as a therapeutic strategy for ALI/ARDS.
急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)是进展迅速、高度致命的临床综合征,其特征是急性进行性缺氧呼吸衰竭。这些疾病导致显著的发病率和死亡率,但目前尚无具体的治疗方法,主要依靠对症治疗和支持性治疗。ALI/ARDS的发病机制与活性氧(ROS)的过量产生和不受控制的炎症反应密切相关,它们共同驱动疾病进展和组织损伤。为了解决这个问题,我们开发了一种新型的ros反应水凝胶微球,包封人脐带间充质干细胞衍生的外泌体,命名为Exo@TK@CaAlg水凝胶微球。该设计结合了硫酮键,赋予微球有效的活性氧清除能力和对氧化应激的特异性反应。Exo@TK@CaAlg微球在体外和体内均具有良好的生物相容性。其强大的活性氧清除能力使其成为缓解ALI的有希望的治疗方法。在临床前研究中,这些微球已经成功地通过雾化输送到ALI小鼠的肺部,它们在减轻氧化应激和炎症方面发挥了关键作用。治疗增强肺毛细血管屏障完整性,减少蛋白质渗出,恢复线粒体功能,并促进巨噬细胞从促炎表型向抗炎表型的转变。这些集体发现突出了Exo@TK@CaAlg水凝胶微球作为ALI/ARDS治疗策略的潜力。
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引用次数: 0
In situ self-assembling rebamipide-based eye drops to promote secretion of mucin for treatment of dry eye 原位自组装利巴米胺滴眼液促进黏蛋白分泌治疗干眼症
IF 10.2 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2026-04-01 Epub Date: 2026-02-05 DOI: 10.1016/j.mtbio.2026.102899
Guanghao Lv , Lei Lei , Jingli Wang, Ying Yang, Yunxiao Zou, Siqi Xie, Ling Wang, Xiaoying Liu, Chenhao Li, Haiqi Wang, Xingyi Li, Jiaqing Wang
Rebamipide is effective for dry eye management, but its insolubility limits formulation development. An optimal design is crucial for patient comfort and maximizing bioavailability. Here we covalently conjugate rebamipide with a peptide motif (FFFYpEH) to generate a peptide-drug conjugate that dramatically improves solubility and enables in situ self-assembly. After topical instillation, the conjugate undergoes enzyme-instructed self-assembly, leading to enhanced drug retention (>25 min) on the ocular surface. In vitro, the conjugate stimulates MUC1 secretion in human corneal epithelial cells and MUC5AC secretion in human conjunctival epithelial cells. In a murine dry eye model, the conjugate demonstrates superior therapeutic efficacy over commercial rebamipide eye drops (Mucosta®), as evidenced by significant symptom alleviation, enhanced corneal epithelial repair, restored tear secretion, and increased conjunctival goblet cell density. Relative to the 14-day non-intervention, treatment of the conjugate results in a threefold increase in corneal epithelium thickness, achieving normal levels. Tear secretion rises nearly fivefold, and conjunctival goblet cell density triples, reaching values comparable to a healthy cornea. Overall, this work addresses the limitations of existing drugs by developing a strategy that not only enhances drug solubility but also promotes ocular retention through in situ self-assembly, thereby offering a promising clinical solution for dry eye management.
利巴米胺对干眼症治疗有效,但其不溶性限制了制剂的发展。最佳设计对于患者舒适度和最大化生物利用度至关重要。在这里,我们将利巴米胺与肽基序(FFFYpEH)共价偶联,以产生肽-药物偶联物,显着提高溶解度并实现原位自组装。局部滴注后,缀合物在酶的引导下进行自组装,从而增强了药物在眼表面的滞留(>25 min)。在体外实验中,该偶联物刺激人角膜上皮细胞MUC1分泌和人结膜上皮细胞MUC5AC分泌。在小鼠干眼模型中,该偶联物的治疗效果优于市售的利巴米胺滴眼液(Mucosta®),可以显著缓解症状,增强角膜上皮修复,恢复泪液分泌,增加结膜杯状细胞密度。相对于14天的非干预治疗,结合物治疗导致角膜上皮厚度增加三倍,达到正常水平。泪液分泌增加近五倍,结膜杯状细胞密度增加三倍,达到与健康角膜相当的值。总的来说,这项工作通过开发一种不仅提高药物溶解度而且通过原位自组装促进眼潴留的策略,解决了现有药物的局限性,从而为干眼症治疗提供了一个有希望的临床解决方案。
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引用次数: 0
The enhanced photothermal therapy against gastric cancer by mitochondria/STAT3-targeted nanoplatform with OXPHOS blocking 利用OXPHOS阻断线粒体/ stat3靶向纳米平台增强光热治疗胃癌
IF 10.2 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2026-04-01 Epub Date: 2026-02-05 DOI: 10.1016/j.mtbio.2026.102891
Wenbin Wang , Lingling Wang , Gege Zhang , Yi Zheng , Qiong Huang , Mi Zou , Yanling Zhang , Shuang Wu , Yajie Sui , Jianda Qiu , Zhao Zhang , Qiaojun Fang , Xianwen Wang , Pingping Liang
Near-infrared (NIR) photothermal therapy (PTT) has provided an innovative modality for the ablation of gastric cancer (GC) with minimized damage to normal tissues. However, the upregulation of heat shock proteins (HSPs) and the abnormal vascularization at the tumor site, as well as the low specificity with the diffusional hindrance of therapeutic agents to cancer cells, severely hamper this mono-therapeutic strategy. To overcome these obstacles, we designed and prepared a mitochondria/STAT3-targeted nanoplatform (ATO/CR NPs), which is self-assembled by Drug Administration (FDA)-approved atorvaquinone (ATO) and NIR phototherapeutic agent CR to fight GC. The ATO/CR NPs exhibit enhanced PTT efficiency owing to the oxidative phosphorylation (OXPHOS) blocking in mitochondria for the downregulation of ATP and HSP based on ATO. More importantly, the ATO from ATO/CR NPs can also specifically target STAT3 in GC cells to restrain proliferation, inhibit angiogenesis, and promote apoptosis. Hence, the multimodal NIR ATO/CR NPs initiate accurate targeting of cancer cells, triggering serious mitochondrial dysfunction and cellular apoptosis to amplify the photo-ablation activity, which provides a promising strategy for GC treatment, warranting further preclinical exploration.
近红外(NIR)光热疗法(PTT)为胃癌(GC)的消融提供了一种创新的方式,同时对正常组织的损伤最小。然而,热休克蛋白(HSPs)的上调和肿瘤部位的异常血管化,以及治疗药物对癌细胞扩散的低特异性,严重阻碍了这种单一治疗策略。为了克服这些障碍,我们设计并制备了线粒体/ stat3靶向纳米平台(ATO/CR NPs),该平台由FDA (FDA)批准的阿托伐醌(ATO)和近红外光治疗剂CR自组装而成,以对抗GC。ATO/CR NPs表现出更高的PTT效率,这是由于线粒体中的氧化磷酸化(OXPHOS)阻断了基于ATO的ATP和HSP的下调。更重要的是,ATO/CR NPs中的ATO还可以特异性靶向GC细胞中的STAT3,从而抑制细胞增殖,抑制血管生成,促进细胞凋亡。因此,多模态NIR ATO/CR NPs启动精确靶向癌细胞,引发严重的线粒体功能障碍和细胞凋亡,以增强光消融活性,为GC治疗提供了一种有希望的策略,值得进一步的临床前探索。
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引用次数: 0
Piezo1 regulates remodeling of skin-derived extracellular matrix by embedded umbilical cord mesenchymal stem cells in a stiffness-dependent fashion Piezo1以刚度依赖的方式调节嵌入脐带间充质干细胞对皮肤来源的细胞外基质的重塑
IF 10.2 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2026-04-01 Epub Date: 2026-01-31 DOI: 10.1016/j.mtbio.2026.102883
Fenghua Zhao , Xue Zhang , Theo Borghuis , Linda A. Brouwer , Janette K. Burgess , Prashant K. Sharma , Martin C. Harmsen
Cells continuously sense and adapt to the mechanical properties of their surrounding extracellular matrix (ECM), yet how human umbilical cord–derived mesenchymal stromal cells (UC-MSCs) mechanotransduce stiffness cues in 3D ECM remains incompletely understood. This knowledge gap limits the rational design of MSC-based regenerative therapies and mechanically instructive biomaterials. Here, using ruthenium-catalyzed photocrosslinked skin-derived ECM hydrogels spanning a physiological to fibrotic stiffness range, we demonstrate that UC-MSCs exhibit distinct, stiffness-dependent remodeling strategies. Soft matrices (1.2 kPa) induced cell-mediated hydrogel contraction, medium stiffness (3.4 kPa, comparable to native skin) supported elongated cell morphology with minimal remodeling, whereas stiff matrices (17.7 kPa) kept seeded UC-MSCs rounded and induced pericellular void formation consistent with localized ECM remodeling. By decoupling geometric contraction from intrinsic ECM turnover using volume-normalized mechanical analyses, we identify the Piezo1 as a key regulator of stiffness-dependent adaptation. Piezo1 expression increased with stiffness, and its inhibition attenuated contraction in soft matrices and prevented stiffness reduction in stiff matrices, indicating that Piezo1 enables MSCs to mechanically adapt across 3D microenvironments. Analysis of matrix metalloproteinase expression revealed stiffness-dependent regulation of MMP2 and MMP14; however, their expression was only marginally affected by Piezo1 inhibition, suggesting that Piezo1 influences ECM remodeling through mechanisms beyond direct regulation of MMP expression. Together, these findings establish a mechanistic framework in which UC-MSCs adapt to 3D ECM stiffness through Piezo1-dependent mechanosensing. This work provides conceptual and practical guidance for the design of mechanically programmable biomaterials, the optimization of MSC-based regenerative strategies, and therapeutic approaches aimed at modulating pathological tissue mechanics such as fibrosis.
细胞不断感知和适应周围细胞外基质(ECM)的机械特性,但人类脐带来源的间充质基质细胞(UC-MSCs)如何在3D ECM中机械转导刚度线索仍不完全清楚。这种知识差距限制了基于msc的再生疗法和机械指导生物材料的合理设计。在这里,使用钌催化光交联皮肤来源的ECM水凝胶,跨越生理到纤维化刚度范围,我们证明UC-MSCs表现出独特的,刚度依赖的重塑策略。软基质(1.2 kPa)诱导细胞介导的水凝胶收缩,中等刚度(3.4 kPa,与天然皮肤相当)支持细长的细胞形态,并具有最小的重塑,而硬基质(17.7 kPa)使种子ucm - mscs保持圆形,并诱导细胞周空隙形成,与局部ECM重塑一致。通过使用体积归一化力学分析将几何收缩与内在ECM翻转解耦,我们确定Piezo1是刚度依赖适应的关键调节器。Piezo1的表达随着刚度的增加而增加,其抑制作用减弱了软基质的收缩,并阻止了硬基质的刚度降低,这表明Piezo1使MSCs能够机械地适应三维微环境。基质金属蛋白酶表达分析显示MMP2和MMP14具有刚度依赖性调控;然而,它们的表达仅受到Piezo1抑制的轻微影响,这表明Piezo1通过直接调节MMP表达以外的机制影响ECM重塑。总之,这些发现建立了一个机制框架,其中UC-MSCs通过piezo1依赖的机械传感适应3D ECM刚度。这项工作为机械可编程生物材料的设计、基于msc的再生策略的优化以及旨在调节病理组织力学(如纤维化)的治疗方法提供了概念和实践指导。
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引用次数: 0
Synergistic 3D-bioprinted scaffold with multi-level adaptability for vascularized bone regeneration via osteogenesis-angiogenesis coupling 通过成骨-血管生成耦合实现血管化骨再生的协同3d生物打印支架
IF 10.2 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2026-04-01 Epub Date: 2026-01-21 DOI: 10.1016/j.mtbio.2026.102837
Ji Yin , Xiaojun Mao , Panpan Shang , Shuo Chen , Guang Yang , Hongtao He , Chuanglong He , Xiaojun Zhou
3D bioprinting enables the fabrication of biomimetic, cell-laden and pro-osteogenic constructs with high precision for bone regeneration. The ability of integrating favorable mechanical strength and multi-material interactive bioactivity in engineered constructs for efficient bone defect repair is still a challenge. Herein, we employed a dual-nozzle synergistic 3D bioprinting technology to fabricate a biocomposite scaffold that integrated interactive soft hydrogel filaments and hard polycaprolactone (PCL)-based filaments by mimicking weave patterns. The multi-material scaffold design aimed at providing features of suitable microstructure and long-term mechanical support, enhanced vascularized bone regeneration for bone repair. Chitosan/hyaluronic acid functionalized mesoporous silica nanoparticles bearing osteogenic protein on the surface and angiogenic drug in the pores were embedded into cell-supportive hydrogel bioink for promoting osteogenesis-angiogenesis coupling. Meanwhile, MgO nanoparticles were incorporated into structure-supportive PCL matrix for improving mechanical strength and compensating angiogenic/osteogenic activities by sustained release of Mg2+. The biocomposite scaffold had good cytocompatibility, and could stimulate in vitro angiogenic behavior and osteogenic differentiation. In vivo experiments revealed that the biocomposite scaffolds significantly enhanced vascularization and promoted bone regeneration on the cranial defect model. Overall, this study has offered a promising strategy for fabricating a multi-level adaptable 3D-bioprinted scaffold for bone defect repair through osteogenesis-angiogenesis coupling.
3D生物打印能够制造具有高精度的骨再生仿生,细胞负载和促骨结构。将良好的机械强度和多材料相互作用的生物活性整合到工程结构中以实现有效的骨缺损修复的能力仍然是一个挑战。在此,我们采用双喷嘴协同3D生物打印技术,通过模拟编织模式,制造了一种生物复合材料支架,该支架集成了相互作用的软水凝胶细丝和硬聚己内酯(PCL)为基础的细丝。多材料支架设计旨在提供合适的微观结构和长期的机械支持,增强血管化骨再生,实现骨修复。将壳聚糖/透明质酸功能化的介孔二氧化硅纳米颗粒包埋在支持细胞的水凝胶生物链中,表面携带成骨蛋白,孔内携带血管生成药物,促进成骨-血管生成耦合。同时,将MgO纳米颗粒加入到结构支持型PCL基质中,通过Mg2+的持续释放来提高机械强度和补偿血管生成/成骨活性。该生物复合支架具有良好的细胞相容性,可刺激体外血管生成行为和成骨分化。体内实验表明,生物复合材料支架可显著增强颅骨缺损模型的血管化,促进骨再生。总的来说,本研究为通过成骨-血管生成耦合修复骨缺损提供了一种有前景的多层适应性3d生物打印支架。
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Materials Today Bio
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