The immunosuppressive tumour immune microenvironment (TIME) is a fundamental barrier that renders "cold" tumours resistant to conventional cancer immunotherapies. Nanozymes, catalytic nanomaterials with enzyme-mimicking...The immunosuppressive tumour immune microenvironment (TIME) is a fundamental barrier that renders "cold" tumours resistant to conventional cancer immunotherapies. Nanozymes, catalytic nanomaterials with enzyme-mimicking activities, have emerged as powerful and versatile agents for reprogramming the TIME and igniting robust antitumour immunity. This review systematically elucidates how nanozymes, through their multi-enzyme catalytic properties, orchestrate a multifaceted attack on the immunosuppressive TIME by regulating reactive oxygen species, alleviating hypoxia, depleting antioxidants, and inducing immunogenic cell death, ferroptosis, and cuproptosis. These catalytic actions collectively promote dendritic cell maturation, enhance cytotoxic T lymphocyte infiltration, and repolarise tumour-associated macrophages toward an M1 phenotype, thereby effectively converting immunologically "cold" tumours into "hot" ones. Furthermore, we deeply analyse the synergistic potential of nanozymes when integrated with established therapies-including immune checkpoint blockade, phototherapy, sonodynamic therapy, chemotherapy, and radiotherapy. Finally, by discussing advanced bioengineered platforms and addressing the ongoing challenges related to biosafety and clinical translation, we envision that nanozyme-based catalytic immunoengineering represents a paradigm-shifting approach for next-generation combinatorial cancer immunotherapy.
Pyrogens, including endotoxins and non-endotoxins, are key factors that impact the safety of parenterally administered drugs as contaminants. Currently, traditional pyrogen detection methods primarily rely on the Rabbit...Pyrogens, including endotoxins and non-endotoxins, are key factors that impact the safety of parenterally administered drugs as contaminants. Currently, traditional pyrogen detection methods primarily rely on the Rabbit Pyrogen Test (RPT) and the Limulus Amebocyte Lysate (LAL) assay, both of which are derived from animal-based systems. However, both methods possess certain limitations. The RPT demonstrates lower reproducibility and a higher false-positive rate compared to the LAL assay; in contrast, the LAL test is limited to detecting endotoxins from Gram-negative organisms. The Monocyte Activation Test (MAT), which is based on monocytes, has emerged as the most promising alternative to traditional pyrogen detection methods. However, the MAT is operationally complex, time-consuming, and exhibits significant individual variability; it typically requires a substantial volume of human blood, thereby considerably limiting its practical application. To overcome these limitations, we developed a rapid pyrogen detection method based on monocytes derived from human embryonic stem cells (hESCs), integrated with a luciferase reporter system. By leveraging the stability and pluripotency of hESCs, we can obtain numerous hESC-derived monocytes (hESC-Mono) through directed in vitro differentiation. These hESC-Mono exhibit batch-to-batch consistency and closely resemble peripheral blood monocytes in functionality. We have demonstrated that hESC-Mono possess sensitive reporting capabilities for at least three types of pyrogens: lipopolysaccharide (LPS), a major component of the cell wall of Gram-negative bacteria; lipoteichoic acid (LTA), a key constituent of the cell wall of Gram-positive bacteria; and fungal Zymosan. Furthermore, we have confirmed that hESC-Mono maintain stable expression of Toll-like receptors, which are among the primary determinants of the reliable detection of pyrogens. Consequently, we have successfully developed and validated a novel pyrogen detection method based on the integration of an in vitro hPSC-directed differentiation system with a luciferase-based reporter assay, thereby offering a promising alternative to traditional pyrogen detection methods.
Arsenic trioxide (ATO) shows limited efficacy against solid tumours, largely because it induces protective autophagy that attenuates its pro-apoptotic activity. Our previous studies established that nanodiamonds (NDs) fu...Arsenic trioxide (ATO) shows limited efficacy against solid tumours, largely because it induces protective autophagy that attenuates its pro-apoptotic activity. Our previous studies established that nanodiamonds (NDs) function as nanoparticle autophagy inhibitors (NAPIs) when delivered systemically, markedly enhancing ATO efficacy in orthotopic liver tumour models by blocking NUPR1-mediated autolysosomal clearance. However, systemic administration remains inefficient in modulating the local autophagic microenvironment within tumours. Here we developed an interventional strategy based on intratumoral injection to assess the feasibility and biosafety of locally blocking autophagic flux while substantially reducing the required ATO dosage, thereby maximising the synergistic anti-tumour effects of NDs and ATO. In HepG2 hepatocellular carcinoma cells, NDs markedly blocked the late stage of autophagic flux, thereby significantly amplifying ATO-induced apoptosis. In a subcutaneous xenograft liver cancer mouse model, intratumoral co-administration of NDs with low-dose ATO achieved ~91% tumour inhibition and effectively eliminated the systemic toxicity associated with high-dose ATO monotherapy. Notably, the synergistic antitumor effect was independent of increased intratumoral ATO accumulation and was driven instead by targeted modulation of the autophagic pathway. Collectively, this study demonstrates a mechanism of localised, nanomaterial-mediated autophagy regulation and offers an efficient, safe strategy for interventional therapy of advanced solid tumours.
Cystatin B (CSTB) is an inhibitor of cysteine proteases, particularly cathepsins. Biallelic loss-of-function mutations in the CSTB gene are causative for progressive myoclonic epilepsy type 1 (EPM1), a neurodegenerative...Cystatin B (CSTB) is an inhibitor of cysteine proteases, particularly cathepsins. Biallelic loss-of-function mutations in the CSTB gene are causative for progressive myoclonic epilepsy type 1 (EPM1), a neurodegenerative disorder characterised by stimulus-sensitive myoclonus and generalised tonic-clonic seizures. Pathomechanisms underlying the disease progression include disturbed proteostasis, increased oxidative stress, neuroinflammation and increased neuronal apoptosis. CSTB downregulation can also lead to cell cycle defects and reduced cell proliferation. Conversely, overexpression of CSTB has been reported to drive proliferation and survival of cancer cells, emphasising the important role of CSTB in cell growth and survival. In the current study, we focused on the role of CSTB in regulating proliferation and survival of EPM1 patients' stem cells. We reprogrammed EPM1 patient fibroblasts into induced pluripotent stem cells (iPSCs), a highly proliferative cell type. Patient cells manifested poor growth and increased apoptosis. Further, EPM1 cells showed oxidative stress, increased lysosomal activity, increased DNA damage and suppressed metabolism. Treatment with antioxidants rescued the growth phenotype and activated metabolism, suggesting oxidative stress as the cause and suppressed metabolism as a protective response. Our data strengthen the central role of CSTB in supporting cell survival and growth. Elucidating the regulatory role of CSTB expression in cell growth can advance our understanding of the pathophysiological mechanisms underlying both EPM1 and cancer and could inform the development of novel therapeutic strategies.
Chronic kidney disease (CKD) has emerged as a critical public health challenge worldwide, and organ donor shortages underscore the urgent need for alternative therapeutic strategies. Advances in stem cell technologies ha...Chronic kidney disease (CKD) has emerged as a critical public health challenge worldwide, and organ donor shortages underscore the urgent need for alternative therapeutic strategies. Advances in stem cell technologies have enabled the generation of kidney organoids, providing innovative platforms to model renal development, investigate disease mechanisms, support drug discovery, and explore applications in regenerative medicine. Yet, limitations such as immature tissue architecture, insufficient vascularisation, and unaddressed safety concerns still hinder their translation into regenerative medicine. In this review, we summarise the fundamentals of kidney development, current differentiation approaches, and the signalling and epigenetic mechanisms underlying organoid lineage specification. We further highlight the roles of bioengineering innovations and single-cell transcriptomics in establishing evaluation frameworks and enhancing structural complexity. We finally emphasise that existing optimisation frameworks, primarily focused on improving differentiation efficiency and enforcing relatively restricted lineage specification, may prove inadequate for bridging the gap to clinical translation. Instead, the most promising paradigm shift involves the convergence of bioengineering modulation and high-resolution functional assessment to facilitate the synchronised advancement of organoid complexity and physiological utility.
Neural innervation is of vital importance for muscle mass and function, and denervation induces progressive muscle atrophy, which lacks effective treatments. Polyamine metabolism is reported to be innervation responsive...Neural innervation is of vital importance for muscle mass and function, and denervation induces progressive muscle atrophy, which lacks effective treatments. Polyamine metabolism is reported to be innervation responsive and involved in denervation-induced muscle atrophy, yet the effects of polyamine in denervated muscle atrophy remain unknown. In this study, using a sciatic nerve transection model, we observed progressive increases in putrescine and spermidine, alongside induction of polyamine metabolism enzymes, coincident with the early rapid atrophy phase post denervation. Pharmacological ODC1 inhibition lowered intramuscular polyamines and improved denervated muscle atrophy and fibrosis. In contrast, spermidine supplementation induced muscle atrophy and atrogene expression in healthy and denervated muscle, implicating spermidine as a pro-atrophic metabolite. Single-nucleus sequencing revealed an expansion of atrophic myonuclei and depletion of type IIb myonuclei post denervation. DFMO reduced the atrophic myonuclear fraction, increased MuSCs abundance, and suppressed FAPs derived FGF signalling dominated by the Fgf7-Fgfr2 axis to maintain MuSCs homeostasis. Taken together, our results demonstrate that dysregulated polyamine metabolism is a key contributor to denervation-induced muscle atrophy, and ODC1 inhibition mitigates muscle atrophy and fibrosis by restraining proteolysis and preserving MuSCs homeostasis, which will provide references for future clinical treatments.
Osteocytes, the central regulators of bone remodelling, are essential for maintaining bone homeostasis. Embedded in a nutrient-limited matrix and burdened by cumulative stress over their exceptionally long lifespan, how...Osteocytes, the central regulators of bone remodelling, are essential for maintaining bone homeostasis. Embedded in a nutrient-limited matrix and burdened by cumulative stress over their exceptionally long lifespan, how osteocytes sustain long-term viability remains elusive. Tunnelling nanotubes (TNTs) are newly described intercellular bridges that enable long-range transfer of organelles and have been implicated in stress adaptation. Here, we provide the first definitive identification of TNTs between cultured osteocytes, which exhibit canonical TNT morphology together with osteocyte-specific features. Functionally, osteocytic TNTs mediate intercellular transfer of membrane-bound cargo, predominantly lysosomes. Under nutrient deprivation, TNT formation and lysosome transfer are both increased, replenishing the lysosomal pool in stressed osteocytes. Transferred lysosomes then fuse with accumulated autophagosomes, thereby restoring impaired autophagic flux and suppressing apoptosis. This cytoprotective effect requires TNT integrity and intact autophagic flux. Although mitochondrial transfer is detectable, it does not confer comparable protection. The findings identify a transcellular autophagy pathway mediated by TNT-dependent lysosome sharing, revealing a previously unrecognized cooperative survival strategy among osteocytes. This work establishes a novel conceptual framework in osteocyte biology and suggests potential therapeutic avenues for bone diseases associated with osteocyte apoptosis and impaired bone remodelling.
Cell Prolif
· 2026 Jun · PMID 42134877
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R. Xu, F. Feng, X. Yu, Z. Liu, and L. Lao, "LncRNA SNHG4 Promotes Tumour Growth by Sponging miR-224-3p and Predicts Poor Survival and Recurrence in Human Osteosarcoma," Cell Proliferation 51, no. 6 (2018): e12515, https:...R. Xu, F. Feng, X. Yu, Z. Liu, and L. Lao, "LncRNA SNHG4 Promotes Tumour Growth by Sponging miR-224-3p and Predicts Poor Survival and Recurrence in Human Osteosarcoma," Cell Proliferation 51, no. 6 (2018): e12515, https://doi.org/10.1111/cpr.12515. The above article, published online on 28 August 2018 in Wiley Online Library (http://onlinelibrary.wiley.com/), has been retracted by agreement between the journal Editor-in-Chief, Qi Zhou; and John Wiley & Sons Ltd. Concerns were raised by a third party regarding duplicated images in multiple figures. An investigation by the publisher found apparent duplications within Figures 3C and 5B, as well as images reused in or taken from other articles by different authors: 2E in Li et al. 2016 (https://doi.org/10.2147/JPR.S118581) and Guo et al. 2019 (https://doi.org/10.1155/2019/4390839); 5F in Zhang et al. 2018 (https://doi.org/10.1590/1414-431X20187439) and Zhu et al. 2019 (https://doi.org/10.18632/aging.102600); and 5B in Chen et al. 2019 (https://doi.org/10.1177/205873841882074) and Zhang et al. 2019 (https://doi.org/10.1007/s10120-019-01018-7). Due to the extent of these apparent duplications, the editor has lost confidence in the results reported, and therefore the article must be retracted. Corresponding author Lifeng Lao agrees with this decision. The other authors did not respond to the publisher's notice of retraction.
Alveolar bone injury represents a prevalent clinical challenge in dentistry, for which stem cell-based therapy has emerged as a promising strategy to promote bone regeneration. N-acetylcysteine (NAC), a potent antioxidan...Alveolar bone injury represents a prevalent clinical challenge in dentistry, for which stem cell-based therapy has emerged as a promising strategy to promote bone regeneration. N-acetylcysteine (NAC), a potent antioxidant, has been shown to modulate the PI3K-AKT signalling pathway and potentially enhance osteogenesis; however, the specific downstream effectors mediating this process remain unidentified. In this study, post-extraction serum metabolomic profiling revealed that alveolar bone injury is accompanied by systemic oxidative stress and metabolic remodelling. Transcriptomic analysis of antioxidant-treated dental stem cells further identified type VI collagen A1 (COL6A1) as a key functional mediator. We subsequently investigated the role of COL6A1 in antioxidant-mediated osteogenesis through immunofluorescence and protein assays, and performed knockdown and in vivo experiments to evaluate its function in oxidative stress regulation and osteogenic differentiation. Our results demonstrated that alveolar bone injury is associated with systemic oxidative stress and global metabolic alterations. In vitro, NAC markedly promoted the osteogenic differentiation of dental follicle stem cells (DFSCs) by activating the PI3K-AKT pathway and upregulating COL6A1. COL6A1 knockdown resulted in elevated reactive oxygen species (ROS) levels, impaired mitochondrial function, and attenuated NAC-mediated osteogenesis. In vivo, NAC-treated DFSCs exhibited enhanced bone healing and extracellular matrix (ECM) deposition in a rat model of alveolar bone injury, effects that were mediated through COL6A1 upregulation. Collectively, these findings demonstrate that NAC enhances osteogenesis in DFSCs via the PI3K-AKT-COL6A1 axis, offering a promising antioxidant-based strategy for stem cell therapies in bone regeneration. Moreover, COL6A1 is essential for maintaining redox homeostasis and represents a potential therapeutic target for improving regenerative outcomes.
Light-inducible activation of FGFR3 induced robust activation of MAPK signaling, promoting proliferation and collagen depositon in induced chondrocytes and prevent the degeneration of osteoarthritic chondrocytes.Light-inducible activation of FGFR3 induced robust activation of MAPK signaling, promoting proliferation and collagen depositon in induced chondrocytes and prevent the degeneration of osteoarthritic chondrocytes.
Wang Y, Li J, Mao X
… +6 more, Wang W, Li Y, Hu X, Zhong J, Zhao F, Wang L
Cell Prolif
· 2026 Jun · PMID 42067961
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Neurological disorders are often devastating and notoriously difficult to repair, creating an urgent need for novel research models and therapeutic strategies. Neural organoids-three-dimensional, self-assembling structur...Neurological disorders are often devastating and notoriously difficult to repair, creating an urgent need for novel research models and therapeutic strategies. Neural organoids-three-dimensional, self-assembling structures derived from stem cells-have emerged as a powerful platform to address this challenge. Supported by enabling technologies like bioreactors and 3D printing, advanced maturation protocols have significantly enhanced their cellular diversity and functional utility. This progress has paved the way for their widespread application in developmental studies, disease modelling, and notably, regenerative medicine. Focusing specifically on the latter, this article reviews how neural organoid transplantation opens new avenues for treating CNS injuries and degeneration. We first elaborate on the development, characteristics, and maturation strategies of neural organoids. We then summarise the translational applications and achievements of transplanting both whole neural organoids and their derived vesicles, analyse the prevailing challenges in the field, and finally, outline future directions to advance the therapeutic potential of this technology.
The mechanisms underlying diabetes-associated cognitive dysfunction (DACD) are not fully understood, and microglial metabolic dysfunction is emerging as a key contributor. This study investigates whether stearoyl-CoA des...The mechanisms underlying diabetes-associated cognitive dysfunction (DACD) are not fully understood, and microglial metabolic dysfunction is emerging as a key contributor. This study investigates whether stearoyl-CoA desaturase 2 (SCD2) alleviates cognitive impairment by modulating microglial lipid metabolism and function. Bioinformatics analysis of a single-cell RNA-seq dataset (GSE201644) identified SCD2 downregulation in diabetic (db/db) microglia. A T2D mouse model underwent hippocampal overexpression of SCD2 via AAV injection. In vitro, high glucose (HG)-treated BV2 microglia-like cells were subjected to SCD2 overexpression or oleic acid (OA) supplementation. Mitochondrial function (OCR, ATP, ETC complexes), lipid droplet accumulation (BODIPY, PLIN2), and inflammation (TNF-α, IL-6) were assessed. Cognitive behaviour (MWM, NOR) and neurophysiology (synaptic markers, neuronal survival) were evaluated. Diabetic microglia exhibited reduced SCD2 expression, impaired oxidative phosphorylation and lipid droplet accumulation (LDAM). SCD2 overexpression or OA rescued mitochondrial function, mitigated lipid droplet accumulation and attenuated inflammation. In vivo, hippocampal SCD2 overexpression attenuated neuroinflammation, preserved synaptic integrity and improved cognition in diabetic mice. SCD2 is essential for maintaining microglial lipid and mitochondrial homeostasis in diabetes. Restoring SCD2 function alleviates neuroinflammation and synaptic deficits, thereby rescuing cognitive impairment, highlighting its therapeutic potential for DACD.
Structural modification of curcumin yielded a novel series of 1,4-pentadien-3-one oxime ether derivatives, among which compound M4 exhibited exceptional antitumor activity against triple-negative breast cancer (TNBC). M4...Structural modification of curcumin yielded a novel series of 1,4-pentadien-3-one oxime ether derivatives, among which compound M4 exhibited exceptional antitumor activity against triple-negative breast cancer (TNBC). M4 demonstrated selective cytotoxicity against TNBC cells, inducing apoptosis and significantly reducing tumour progression and pulmonary metastasis in a 4 T1 orthotopic mouse model at doses lower than paclitaxel. Mechanistic investigations revealed that M4 directly targets heat shock protein 70 (HSP70) by binding to its ATPase domain, triggering lysosomal dysfunction characterized by pH neutralization, reduced acid sphingomyelinase activity, lipid accumulation, and cathepsin leakage. These alterations led to disruption of lysosomal function leading to impaired autophagic degradation, as evidenced by the accumulation of autophagosomes and increased levels of LC3-II/p62. Knockdown of the HSP70 gene abolished M4-induced lysosomal damage and its anti-TNBC effects, confirming HSP70 as the functional target of M4. Furthermore, inhibition of HSP70 suppressed TNBC metastasis by regulating autophagy-mediated epithelial-mesenchymal transition and stemness. M4 demonstrated selective cytotoxicity against TNBC cells, induced apoptosis, and significantly inhibited tumour progression and pulmonary metastasis in a 4 T1 orthotopic mouse model at doses lower than those of paclitaxel. The combination of M4 and paclitaxel showed synergistic anti-TNBC efficacy both in vitro and in vivo, effectively counteracting chemotherapy-induced HSP70 upregulation and autophagic activation. The study not only identifies M4 as a promising therapeutic candidate but also validates HSP70-targeted therapy as an effective combinatorial strategy with conventional chemotherapy for the treatment of TNBC.
Intervertebral disc degeneration (IDD) represents a major global health challenge, primarily due to the inability of current therapies to reverse the progressive loss of nucleus pulposus (NP) tissue and function. Transpl...Intervertebral disc degeneration (IDD) represents a major global health challenge, primarily due to the inability of current therapies to reverse the progressive loss of nucleus pulposus (NP) tissue and function. Transplanting bioactive substitutes offers potential for overcoming this limitation. However, current strategies fail to generate large-sized, functional human NP substitutes, impeded by a fundamental trade-off: the incapacity to simultaneously achieve scalable expansion and maintain the essential cellular phenotype. Here, we found that human platelet lysate (hPL) acts not merely as a growth supplement but as a powerful metabolic primer, driving robust proliferation of human NP cells (hNPCs) while remarkably preserving a mature NP phenotype. This was demonstrated through sustained expression of aggrecan (ACAN) and collagen type II (COL2). Crucially, this metabolic shift allowed us to create a high-quality, homogeneous NP macromass exceeding 2 mm in size, which exhibited superior mechanical integrity and successfully avoided the common problem of necrotic core formation. In vivo validation demonstrated significantly larger grafts with markedly enhanced ACAN and COL2 deposition, confirming the functional superiority of the constructs. Mechanistically, transcriptomic analysis revealed that hPL specifically enhanced fatty acid oxidation (FAO), with this energy metabolism shift serving as the primary driver enabling both rapid growth and phenotypic stability. Ultimately, the hPL-primed NP macromass demonstrated exceptional efficacy in repairing degenerated discs in situ. Our work introduces a novel and potent paradigm for IDD treatment by harnessing the principle of metabolic priming to generate scalable and functional NP substitutes, effectively bridging a critical gap in disc regeneration therapy.
Fu B, Huang W, Liu Y
… +29 more, Wang L, Liu Y, Cao J, Duan W, Ma A, Zhao H, Niu S, Hu S, Li Q, Zhang Y, Peng Y, Yu X, Yu J, Wei J, Zhang Y, Hua G, Liu X, Wang C, Na T, Zhao Y, Zhou J, Xiang P, Wu Z, Chen Q, Zhai P, Gao H, Hao J, Zhao T, Wang J
The overlap HPLC chromatograms of ATP standard (red) and ATP in cells (blue). Poroshell 120 EC-C18 (3 × 150 mm, 2.7 μm), 25°C, pH 6.8 buffer solution of 0.05 mol/L KHPO - 0.05 mol/L KHPO (V:V = 1:1) as mobile phase, 0.6...The overlap HPLC chromatograms of ATP standard (red) and ATP in cells (blue). Poroshell 120 EC-C18 (3 × 150 mm, 2.7 μm), 25°C, pH 6.8 buffer solution of 0.05 mol/L KHPO - 0.05 mol/L KHPO (V:V = 1:1) as mobile phase, 0.6 mL/min, 254 nm.
Mitochondria play central roles in cellular energy metabolism and signal transduction, and maintenance of mitochondrial homeostasis is essential for proper cellular function. Rather than being regulated by individual gen...Mitochondria play central roles in cellular energy metabolism and signal transduction, and maintenance of mitochondrial homeostasis is essential for proper cellular function. Rather than being regulated by individual genes alone, mitochondrial homeostasis is governed by coordinated functional modules, including glucose and lipid metabolism, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), calcium handling, mitochondrial dynamics, mitochondrial reactive oxygen species (mtROS) regulation, and mitochondrial transcription and translation. However, how perturbation of these modules reshapes cellular states remains incompletely understood. Here, we combined targeted chemical perturbations with single-cell RNA sequencing (scRNA-seq) to systematically profile transcriptional responses to inhibition of core mitochondrial functional modules. Comparative analyses revealed both shared and module-specific transcriptional programs, including recurrent co-expression patterns across distinct perturbations. Analysis of mitochondrial gene expression across conditions implicated mtROS as an important regulator of mitochondrial respiratory chain (MRC) gene expression, potentially acting through activation of the mitochondrial integrated stress response (mtISR). Further comparative analysis of perturbations targeting individual MRC complexes uncovered distinct transcriptional and cellular consequences among complexes. Examination of cell-cycle dynamics showed that mitochondrial perturbations generally suppress cell proliferation; inhibition of most MRC complexes was associated with G1-phase arrest, whereas perturbation of complex III preferentially led to G2/M-phase arrest, potentially reflecting differential engagement of p53-associated signaling pathways. Finally, our analysis revealed both conserved and divergent transcriptional responses to mitochondrial perturbations between human and mouse cells. Together, these findings establish a systematic single-cell framework for dissecting mitochondrial functional modules and highlight both shared and function-specific principles by which mitochondrial perturbations influence cellular transcriptional states.
The therapeutic application of cytotoxic proteins like ribonuclease A (RNase A) is hindered by their systemic toxicity. Here, we engineer a protein-structure-directed zeolitic pyrimidine framework (ZPF) as a superior nan...The therapeutic application of cytotoxic proteins like ribonuclease A (RNase A) is hindered by their systemic toxicity. Here, we engineer a protein-structure-directed zeolitic pyrimidine framework (ZPF) as a superior nanocarrier that co-encapsulates and stabilizes a ROS-responsive RNase A prodrug (RNBC) and a GPX-1-targeting DNAzyme with high efficiency. This DZ-RNBC@ZPF nanocomplex, camouflaged with a 4T1 cell membrane, ensures tumour-specific delivery and lysosomal degradation. The acidic environment triggers framework dissolution, releasing Zn to activate the DNAzyme. The DNAzyme downregulates GPX-1, amplifying intracellular HO, which in turn cleaves the NBC group to activate the RNase A prodrug precisely within target cells. This coordinated intracellular cascade-from material degradation to enzymatic ROS amplification and prodrug activation-induces significant apoptosis in 4T1 cells and potently suppresses tumour growth in vivo. Our work establishes ZPF as an enabling platform for the co-delivery of bioactive macromolecules and presents a novel therapeutic strategy based on a synergistic protein prodrug-DNAzyme circuit.
He A, Lin X, Qian X
… +42 more, Mu J, Tao Z, Gu J, Wang Y, Han T, Zhao H, Wang Y, Zhang J, Zhou Z, Xing L, Zhou C, Zhu D, Liu Z, Chen G, Zhou Q, Wang X, Zhao S, Liu X, Cao D, Yu B, Liu Z, Wang J, Niu G, Wei G, Chen M, Wang W, Kang X, Zhou J, Gong S, Xie Y, Zhang J, Kong X, Dong C, Zou Y, Tang L, Ma A, Xiong H, Liu X, Zhao T, Hao J, Xiao X, Xiang D
This guideline establishes a comprehensive framework for the application of patient-derived pancreatic cancer organoids. It outlines the stringent technical requirements and testing methods necessary to ensure high fidel...This guideline establishes a comprehensive framework for the application of patient-derived pancreatic cancer organoids. It outlines the stringent technical requirements and testing methods necessary to ensure high fidelity to the original tumor tissue, including morphological assessment, pathological biomarker expression (e.g., CK19, CK7), and genetic concordance (e.g., NRG1, KRAS). By standardizing protocols for in vitro culture, microbiological safety, and STR authentication, this consensus aims to ensure the reproducibility, safety, and stability of organoid models, thereby accelerating their integration into basic research, drug discovery, and precision medicine.