Journal of Nanobiotechnology最新文献

{"title":"Mesenchymal stem cell-derived extracellular vesicles attenuate liver transplantation-induced ischemia/reperfusion injury by suppressing hepatocellular complement C5 expression.","authors":"Yasong Liu, Jiaqi Xiao, Zhengqi Wu, Feng Zhang, Qiang You, Haitian Chen, Jiebin Zhang, Yang Yang, Tingting Wang, Shuhong Yi, Rong Li, Jun Zheng","doi":"10.1186/s12951-026-04388-0","DOIUrl":"https://doi.org/10.1186/s12951-026-04388-0","url":null,"abstract":"<p><strong>Background & aims: </strong>Hepatic ischemia-reperfusion injury (HIRI) is an unavoidable complication of liver transplantation (LT) that drives allograft dysfunction and mortality. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show therapeutic promise, yet their actions within the hepatic network remain incompletely defined. We investigated how MSC-EVs protect against LT-induced HIRI, focusing on intercellular communication and complement-mediated inflammation.</p><p><strong>Methods: </strong>Single-cell RNA sequencing, single-nucleus ATAC-seq, and spatial transcriptomics were performed in rat LT and mouse HIRI livers with or without MSC-EV treatment. Cell migration assays, AAV-mediated overexpression, and PTPN13-knockdown MSC-EVs were used to prove cellular function and mechanisms.</p><p><strong>Results: </strong>MSC-EVs attenuated HIRI, improving liver function and reducing histologic injury and hepatocyte apoptosis. Single-cell analyses showed selective curtailment of mononuclear phagocyte and neutrophil recruitment to injured liver. Mechanistically, HIRI induced hepatocyte C5 and C5a, which engaged C5aR1 on mononuclear phagocytes and neutrophils to drive chemotaxis. Consistent with this pathway, MSC-EVs delivered PTPN13 to hepatocytes, lowering C5 and promoting ERK1/2 dephosphorylation and enhanced C/EBPα activity. Elevated C/EBPα activity directly suppressed C5 transcription, whereas PTPN13-depleted MSC-EVs showed diminished efficacy.</p><p><strong>Conclusions: </strong>We present a single-cell multi-omics atlas of MSC-EV therapy across rat LT and mouse HIRI, supported by clinical data. MSC-EVs mitigated HIRI by lowering hepatocyte C5 and reducing mononuclear phagocyte and neutrophil recruitment. MSC-EV delivery of PTPN13 dephosphorylated ERK1/2 and enhanced C/EBPα, repressing hepatocyte C5 and dampening C5a-C5aR1 signaling. These findings position MSC-EVs as a translational nanotherapy to improve graft outcomes after LT.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":" ","pages":""},"PeriodicalIF":12.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral alginate microspheres deliver Rg3/aspirin liposomes to modulate foam cells and gut microbiota in atherosclerosis.","authors":"Yong-Bo Liu, Jing-Tian Zhang, Jun-Nan Hu, Shen Ren, De-Yang Huo, Ling-Jie Song, Wei Li","doi":"10.1186/s12951-026-04478-z","DOIUrl":"https://doi.org/10.1186/s12951-026-04478-z","url":null,"abstract":"<p><p>Atherosclerosis is a complex pathology driven by chronic inflammation, lipid accumulation, and thrombosis, necessitating multi-pathway therapeutic strategies. Herein, we engineered an oral multi-stage platform (RALM) comprising aspirin (Asp) and ginsenoside Rg3 co-loaded phosphatidylserine (PS) liposomes (RA-Lipo) encapsulated within sodium alginate microspheres. Physicochemical and biological evaluations revealed that the incorporation of Rg3 into the lipid bilayer as a cholesterol substitute yielded uniform RA-Lipo, which exhibited colloidal stability, intestinal epithelial transport, and prolonged systemic circulation. The electrosprayed alginate matrix functioned as a pH-responsive barrier, preventing premature degradation in the gastric environment and enabling the sustained release of RA-Lipo within the intestinal tract. Following oral administration in HFD-induced ApoE^-/- mice, integrated 16 S rRNA sequencing and untargeted metabolomics revealed that RALM reshaped HFD-induced dysbiosis and modulated the metabolic profile, characterized by an increased Bacteroidetes/Firmicutes (B/F) ratio along with decreased prostaglandin E2 (PGE2) and elevated arginine levels. Fluorescence tracking experiment further demonstrated that the liberated RA-Lipo accumulated within aortic plaques. At the cellular level, RA-Lipo activated the PPARγ pathway, thereby enhancing cholesterol efflux and inhibiting foam cell formation. Ultimately, this synergistic regulation translated into remarkable therapeutic efficacy, effectively reducing plaque burden, suppressing pro-inflammatory cytokines, and demonstrating superior anticoagulant activity. Supported by a favorable safety evaluation, this RALM platform offers a comprehensive approach for alleviating atherosclerosis progression.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":" ","pages":""},"PeriodicalIF":12.6,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecularly sculpted NIR-II nano-igniter converts local photothermal heat into systemic antitumor vaccination.","authors":"Qihang Ding, Tingting Liu, Chunbai Xiang, Qian Wang, Meiqin Li, Yao Sun, Ruiping Zhang","doi":"10.1186/s12951-026-04361-x","DOIUrl":"https://doi.org/10.1186/s12951-026-04361-x","url":null,"abstract":"<p><p>Photothermal therapy (PTT) holds transformative potential for precision cancer treatment, yet clinical translation remains constrained by the scarcity of molecularly defined, biocompatible, and efficiently NIR-absorbing photothermal agents (PTAs). Here we report a rational donor-acceptor-donor (D-A-D) framework that delivers ultrasmall organic PTAs with record photothermal conversion efficiencies (49.8%) and intrinsic immunogenic cell death (ICD) activity. The design exploits 6,7-diphenyl-[1,2,5]thiadiazolo[3,4-g]quinoxaline as a π-extended, multi-nitrogenated acceptor core flanked by trifluoromethyl groups to deepen the LUMO, while methoxylated triphenylamine donors intensify intramolecular charge-transfer and suppress radiative decay. Nanoprecipitation furnishes monodisperse nanoparticles that exhibit intense NIR-II absorption, exceptional photostability across five hyperthermic cycles, and lysosome-directed uptake. In vitro, single-dose FTPA NPs plus 808-nm laser irradiation trigger mitochondrial depolarization, G0/G1 arrest, and apoptosis in > 70% of 4T1 cells while releasing abundant ATP and surface calreticulin-canonical ICD signals. A prophylactic vaccination model corroborates these molecular cues: mice primed with FTPA-NP-treated tumor cells reject contralateral challenge, achieving > 90% long-term survival, expansion of cytotoxic CD8⁺ T cells (≈ 70% activation), and suppression of Tregs (≈ 3%). No systemic toxicity or off-target pathology is observed. This study establishes a chemically tunable, metal-free PTA platform that synergizes thermal ablation with systemic anti-tumor immunity, providing a versatile scaffold for next-generation precision immuno-photothermal medicine.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":" ","pages":""},"PeriodicalIF":12.6,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plant-derived nanovesicles: the intelligent nanoplatforms for therapeutics and drug delivery.","authors":"Shuang Du, Dan Jia, Guohui Liang, Yonghui Dou","doi":"10.1186/s12951-026-04484-1","DOIUrl":"https://doi.org/10.1186/s12951-026-04484-1","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are cell-secreted phospholipid bilayer vesicles that play a key role in intercellular communication by transporting molecular cargo and engaging in surface-level signaling. Due to their intrinsic biological features, EVs not only reflect the functional attributes of their originating cells but also hold promise as both therapeutic agent and natural carriers for targeted delivery. In recent years, plant-derived nanovesicles (PDNVs) containing bioactive molecules have attracted the attention of researchers because of their better biocompatibility, low immunogenicity, wide range of sources, and ability to act as natural therapeutic agents for diseases. PDNVs play an increasingly important role in human-plant interactions, as they are able to enter the human system and deliver effector molecules to cells, which in turn modulate cellular signaling pathways. PDNVs play a critical role in human health and disease. This review provides a comprehensive overview of PDNVs, encompassing their biogenesis, methods of isolation and purification, physicochemical characterization, stability, and storage strategies. It further explores their routes of administration, internalization, and biodistribution as therapeutic agents, highlighting their potential in the treatment of conditions such as inflammation, cancer, tissue regeneration, viral infections, liver and brain disorders, and osteoporosis. Lastly, the review examines current clinical applications of PDNVs and the key challenges hindering their broader implementation. We look forward to further exploration of the functions of PDNVs to facilitate their clinical translation and increase their benefits in humans.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":" ","pages":""},"PeriodicalIF":12.6,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-throughput human microfluidic organoid-on-a-chip platform for modeling liver diseases and screening nanotherapeutics.","authors":"Defu Kong, Shihang Yu, Janette Heegsma, Tjasso Blokzijl, Tian Qin, Yixiao Pan, Hans Blokzijl, Vincent E de Meijer, Yourong Duan, Klaas Nico Faber, Qiang Xia, Kang He","doi":"10.1186/s12951-026-04477-0","DOIUrl":"https://doi.org/10.1186/s12951-026-04477-0","url":null,"abstract":"<p><strong>Background: </strong>Human liver tissue-derived organoids recapitulate key hepatic phenotypes but are commonly maintained under static conditions, whereas microfluidic organ-on-chip systems provide controllable perfusion and mass transport. Scalable integration of human liver tissue-derived organoids into a perfused, human-relevant Liver-on-Chip remains limited.</p><p><strong>Results: </strong>We combined healthy human liver tissue-derived organoids with a high-throughput three-lane OrganoPlate microfluidic format to establish a perfused organoid Liver-on-Chip (HepLoC) featuring 3D luminal tubules under continuous flow. After hepatocyte-directed differentiation under perfusion, bioengineered HepLoC formed mature hepatocyte-like architectures with increased mature hepatocyte marker proteins, enrichment of hepatic transcriptomic signatures, and functional bile canaliculi. As a proof-of-concept for drug-induced liver injury, troglitazone induced dose-dependent hepatocyte injury accompanied by tight-junction disruption, MRP2 mislocalization, and impaired bile acid export, recapitulating key features of cholestatic liver injury. To model metabolic liver disease, free fatty acids triggered lipid droplet accumulation, increased triglycerides and reactive oxygen species, and upregulated lipogenic and inflammatory genes while largely preserving viability, consistent with early-stage metabolic dysfunction-associated fatty liver disease. The high-throughput HepLoC format further enabled parallel testing of reference hepatotoxic drugs and curcumin liposomes by reduced lipid accumulation in fatty-acid-treated HepLoC with minimal hepatotoxicity.</p><p><strong>Conclusions: </strong>Our perfused, organoid-based microfluidic Liver-on-Chip recapitulates essential human liver structure and function and enables integrated, parallel evaluation of hepatotoxicity and optimization of nanotherapeutic strategies, which deciphers the mechanisms of liver diseases, bridging the gap between preclinical research and clinical translation.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":" ","pages":""},"PeriodicalIF":12.6,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional ferritin-mimetic iron homeostasis nanoregulator to suppress ferroptosis and promote angiogenesis as a new therapeutic strategy for diabetic wound healing.","authors":"Yumeng Zheng, Fupeng Li, Ao Zheng, Tanjun Deng, Haoyu Wang, Li Yan, Yifei Yin, Wenli Lu, Lingyan Cao, Zhengyu Shen","doi":"10.1186/s12951-026-04406-1","DOIUrl":"https://doi.org/10.1186/s12951-026-04406-1","url":null,"abstract":"<p><p>Diabetic foot ulcer (DFU) is among the most severe complications of diabetes, where delayed healing is closely linked to impaired angiogenesis and ferroptosis-associated iron dysregulation. However, the underlying molecular mechanisms remain incompletely understood, and effective interventions specifically targeting DFU healing are still lacking. Here, we present a biomimetic iron homeostasis rebalancing nanoregulator, atRA/GOQDs nanoparticles (RG NPs), designed to rebalance pathological iron dynamics and restore the angiogenic microenvironment in chronic diabetic wounds. RG NPs integrate two complementary regulatory modes: labile iron sequestration mediated by GOQDs and intracellular iron buffering reinforcement through atRA-induced ferritin upregulation. This dual-mode strategy actively reconstructs iron equilibrium, suppresses lipid peroxidation at its source, and inhibits endothelial ferroptosis, thereby facilitating angiogenic function and tissue repair. In vitro, RG NPs exhibited robust labile iron sequestration capacity, enhanced ferritin expression, attenuated ferroptosis injury, and restored endothelial angiogenic activity. In db/db mice, local application of RG NPs significantly accelerated wound closure. Collectively, our work reveals an iron homeostasis-angiogenesis regulatory axis and offers a system-level therapeutic strategy that highlights a conceptual shift from conventional antioxidant and simple iron chelation strategies toward a coordinated iron homeostasis regulation in chronic diabetic wound repair.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":" ","pages":""},"PeriodicalIF":12.6,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PDA@MnO_x nanozyme-engineered mesenchymal stem cells for severe acute pancreatitis therapy via modulation of ROS-inflammation-microbiota homeostasis.","authors":"Zinan Zhao, Muladili Mutailipu, Tianxiao Mei, Ran Cui, Yongkun Wang, Fuguo Liu, Chunxiu Dong, Wenwen Jia, Zhongmin Liu, Bo Chen, Wenjun Le, Yihui Hu","doi":"10.1186/s12951-026-04487-y","DOIUrl":"https://doi.org/10.1186/s12951-026-04487-y","url":null,"abstract":"<p><p>Severe acute pancreatitis (SAP) is a life-threatening inflammatory disorder with an approximate mortality rate of 40%. Current therapeutic approaches fail to address its complex pathological microenvironment, necessitating novel synergistic strategies. Although mesenchymal stem cells (MSCs) exhibit therapeutic potential, their efficacy is significantly compromised by SAP-associated oxidative stress, hyperinflammation, and gut dysbiosis. Herein, we engineered MSCs with antioxidant nanozyme PDA@MnO_x, named PDA@MnO_x-MSCs (Abbr. E-MSCs), to establish a regulatory network for SAP therapy. The PDA@MnO_x nanozymes not only scavenge reactive oxygen species (ROS) to protect MSCs from oxidative damage but also enable in vivo T₁-weighted MRI tracking. E-MSCs demonstrated enhanced anti-inflammatory effects, evidenced by reduced levels of TNF-ɑ and IL-6, and restored gut microbiota homeostasis, characterized by increased Bacteroidetes abundance. This further alleviated pancreatic necrosis and systemic inflammation. Notably, the synergistic interaction among PDA@MnO_x nanozymes, MSCs, and the pathological microenvironment restored ROS-inflammation-microbiota homeostasis, significantly improving SAP outcomes. This study provides a multifunctional strategy integrating therapeutic efficacy, in vivo tracking, and gut microbiota modulation for SAP treatment.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":" ","pages":""},"PeriodicalIF":12.6,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ZIF-8 nanoplatform targeted delivery of IFI44 siRNA to suppress bladder cancer development via modulating the PI3K/AKT signaling pathway.","authors":"Chao Zhu, Mengwei Liu, Xiaohua Liu, Sifan Zhang, Yun He, Meng Chen, Haoxuan Huang, Kuai Yu, Aiping Le","doi":"10.1186/s12951-026-04419-w","DOIUrl":"https://doi.org/10.1186/s12951-026-04419-w","url":null,"abstract":"<p><p>Malignant progression of bladder cancer (BC) is frequently caused by its complex molecular regulation, leading to unfavorable clinical outcomes. Our research indicates that interferon-induced protein 44 (IFI44) is significantly overexpressed in BC, thereby facilitating its malignant progression. Mechanistically, BC's progression is impeded by the knockdown of IFI44, partially due to the inhibition of the PI3K/AKT signaling pathway. In addition, we constructed a Zeolitic Imidazolate Framework-8 (ZIF-8) nanoplatform, incorporating ZIF-8@siIFI44, ZIF-8@siIFI44@PEG and ZIF-8@siIFI44@PEG-RGD. Subsequent experiments demonstrated that ZIF-8@siIFI44 and ZIF-8@siIFI44@PEG possess anti-tumor property, while ZIF-8@siIFI44@PEG-RGD exhibited enhanced anti-tumor efficacy due to the inclusion of RGD targeting peptides which especially target tumors. Additionally, our study confirmed that the ZIF-8 nanoplatform enables targeted delivery of IFI44 siRNA, therefore preventing BC development partially by influencing the PI3K/AKT signaling pathway. Our findings identify IFI44 as an element that aids in the malignant development of BC, emphasizing its promise as a target for therapy.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":" ","pages":""},"PeriodicalIF":12.6,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AIEgen-mediated integration of plain DNA and hydrophobic compounds enabling three-in-one nanosystems for carrier-free delivery.","authors":"Yingqi Liang, Xianggui Yin, Yiming Ding, Zi'ang Yang, Shi Cao, Minjiang Chen, Lifei Zheng, Qing Liu, Jiansong Ji, Shiji Fang","doi":"10.1186/s12951-026-04485-0","DOIUrl":"https://doi.org/10.1186/s12951-026-04485-0","url":null,"abstract":"<p><p>DNA has been serving as a powerful and programmable vector for drug delivery, yet facile strategies for the direct loading of hydrophobic payloads onto DNA vehicles are still lacking but highly demanded. In this work, we report an AIEgen-mediated approach for the integration of plain DNA and hydrophobic molecules into nanospheres upon heating treatment. The broad applicability of this strategy is established by loading nine different hydrophobic molecules with high loading capacity, including six therapeutic drugs and three fluorescent dyes. Owing to the compact configuration, the nano-systems show superior stability under physiologically relevant conditions while the AIEgen displays significantly enhanced fluorescent signal and reactive oxygen species-generating ability upon light irradiation. In vitro studies validate the successful cellular delivery of the nanosystems, as evidenced by effective cell staining with fluorescent dyes and synergistic cytotoxicity from the combined action of loaded drugs and AIEgen-mediated photodynamic therapy (PDT). Finally, by using sorafenib and an antisense oligonucleotide (ASO), we demonstrate the synergistic antitumor efficacy of the nanodrug in vitro and in vivo: while ASO prolongs intracellular drug retention by down-regulating the efflux factor P-glycoprotein, sorafenib can amplify the PDT efficacy of the AIEgen by depleting glutathione and glutathione peroxidase 4. Therefore, our work establishes an effective AIEgen-mediated and heat-promoted strategy for creating multifunctional nanosystems, which may find widespread application in carrier-free delivery for disease theranostics.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":" ","pages":""},"PeriodicalIF":12.6,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomimetic nanoparticles facilitating the functional engraftment of lung epithelial stem cells for silicosis therapy.","authors":"Wenyue Zhang, Anning Yang, Yi Guo, Rui Bao, Siwei Zou, Ran An, Yuanyuan Pang, Mengsi Xiao, Huning Zhang, Sirong Chang, Yideng Jiang, Zhihong Liu, Yue Sun","doi":"10.1186/s12951-026-04377-3","DOIUrl":"https://doi.org/10.1186/s12951-026-04377-3","url":null,"abstract":"<p><p>Silicosis is an irreversible, progressive occupational lung disease caused by chronic inhalation of crystalline silica (SiO₂), with no approved disease-modifying therapies currently available. Its pathological hallmark is a hostile fibrotic microenvironment driven by excessive reactive oxygen species (ROS), chronic inflammation, and mitochondrial dysfunction in alveolar epithelial type 2 (AEC2) cells; this microenvironment is the primary bottleneck for stem cell-based silicosis therapy, as it severely impairs the engraftment of exogenous AEC2 cells. Metformin (Met) exerts mitochondria-protective effects to preserve AEC2 function, but its clinical translation for silicosis is limited by low oral bioavailability and non-specific systemic distribution. Here, we developed a ROS-responsive biomimetic liposome (TK-PSBs@Met, also termed TPM NPs) for targeted Met delivery to AEC2s in fibrotic lungs, via a design combining pulmonary surfactant (PS)-mediated AEC2 targeting and thioketal (TK)-based ROS-triggered on-demand drug release. In vitro, TPM NPs reversed SiO₂-induced epithelial-mesenchymal transition (EMT), suppressed fibrotic and inflammatory responses, and restored mitochondrial function in A549 cells, a well-established AEC2 cell model. In vivo, TPM NPs significantly boosted the functional engraftment of TdTomato⁺ AEC2 stem cells, promoted alveolar regeneration, and attenuated collagen deposition and inflammation in SiO₂-induced silicosis mice. Mechanistically, TPM NPs mitigated silicotic fibrosis via a dual synergistic mechanism: remodeling the hostile fibrotic microenvironment and activating the AMPK/PGC-1α/NRF1/TFAM signaling axis to restore AEC2 mitochondrial biogenesis. Collectively, this TPM NP-AEC2 combinatorial therapy offers a translatable precision strategy for silicosis treatment and establishes a new paradigm for nanomedicine-augmented stem cell therapy in refractory fibrotic lung diseases.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":" ","pages":""},"PeriodicalIF":12.6,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}