Luo J, Shi Y, Ji D
… +11 more, Jiao P, Wang F, Zhang J, Wang X, Wang Y, Chen Z, Yu M, Xiao S, Wang Q, Zhou D, Zhang C
Biomaterials
· 2026 Jun · PMID 42308604
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Adeno-associated virus (AAV) vectors are a promising platform for liver-directed gene therapy, yet their clinical translation is hindered by limited cell-type specificity and dose-dependent immune responses. Here, we rep...Adeno-associated virus (AAV) vectors are a promising platform for liver-directed gene therapy, yet their clinical translation is hindered by limited cell-type specificity and dose-dependent immune responses. Here, we report a chemical biology strategy for programmable, site-defined glycan installation on intact AAV capsids via genetic code expansion and biorthogonal chemistry. This approach enables precise conjugation of triantennary N-acetylgalactosamine (GN), a model ligand of the hepatocyte-specific receptor ASGPR1 for proof of concept, to AAV2, AAV8, and AAV-DJ capsids, overcoming the stochastic nature of conventional modifications. The resulting GN-modified AAVs (AAV-GN3) exhibit enhanced hepatocyte-specific transduction, reduced susceptibility to pre-existing neutralizing antibodies, and attenuated innate and adaptive immune activation. Importantly, AAV-GN3 mediates hepatocyte-restricted FOXA2 and FIX expression, alleviating liver fibrosis and hemophilia in mice, and its properties of weakening immune activation suggest potential for AAV-seropositive patients or repeated administration scenarios. These results establish a modular, precise platform for AAV glycoengineering, advancing the development of safer and more effective liver-targeted gene therapies.
Zhong Y, Zhang K, Li X
… +7 more, Li Z, Huang X, Qiu Z, Nie J, Wang J, Li S, Cheng H
Biomaterials
· 2026 Jun · PMID 42308603
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Despite its critical role in treating localized breast cancer, radiotherapy (RT) rarely provokes systemic immune responses or abscopal effects. In this work, immunological profiling reveals that RT upregulates CD47 and P...Despite its critical role in treating localized breast cancer, radiotherapy (RT) rarely provokes systemic immune responses or abscopal effects. In this work, immunological profiling reveals that RT upregulates CD47 and PD-L1 expressions in tumor cells and promotes the accumulation of M2-type tumor-associated macrophages (TAMs), suggesting a potential immunosuppressive mechanism that restricts abscopal responses. To overcome this limitation, a legumain-activated radio-immunological synergist (LARIS) is rationally designed to amplify RT-induced abscopal effects through dual CD47/PD-L1 blockade and TAM repolarization. LARIS is constructed from a bispecific immune checkpoint blockade chimeric peptide (BiCCP) linking CD47-and PD-L1-blocking peptides via a legumain-cleavable linker, and co-formulated with the Toll-like receptor 7/8 agonist R848. Within the tumor microenvironment, abundant legumain can cleave LARIS to release R848 together with the checkpoint blockade peptides, thereby reprogramming TAMs toward an M1 phenotype and mitigating CD47/PD-L1-mediated immune evasion. Both in vitro and in vivo studies demonstrated that LARIS significantly enhances systemic antitumor immunity and effectively induces abscopal responses of RT, thus suppressing the growth of distant and rechallenged tumors. Overall, this work offers a promising strategy to counteract RT-induced immunosuppression and potentiate abscopal effects for improved breast cancer therapy.
Gao Y, Zhuang Y, Liu E
… +3 more, Chang F, Ding J, Chen X
Biomaterials
· 2026 May · PMID 42302585
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Stiffness-adaptive gradient scaffolds that provide precise mechanobiological cues are highly desirable for coordinated osteochondral repair. However, most existing scaffolds remain mechanically static and spatially homog...Stiffness-adaptive gradient scaffolds that provide precise mechanobiological cues are highly desirable for coordinated osteochondral repair. However, most existing scaffolds remain mechanically static and spatially homogeneous after implantation, and therefore fail to recapitulate the adaptive stiffening and depth-dependent heterogeneity of native osteochondral interface. Herein, an endogenous alkaline phosphatase (ALP)-responsive hydrogel is developed to translate the native depth-dependent ALP activity of osteochondral tissue into in situ mechanical remodeling. A phosphorylated peptide is covalently grafted onto gelatin methacryloyl and then photo-cross-linked to form a primary network. ALP-mediated dephosphorylation subsequently induces β-sheet-rich assembly of the grafted phosphorylated peptides, establishing a secondary physical network that increases the unconfined compressive modulus from 76.11 to 240.75 kPa and gives rise to a depth-aligned stiffening profile. These evolving mechanical cues regulate stem cell fate through adhesion-associated mechanotransduction, centered on focal adhesion kinase, Rho-associated kinase, and Hippo-Yes-associated protein signaling, with softer regions favoring chondrogenesis and stiffer regions promoting osteogenesis. In a rabbit osteochondral defect model, the stiffness-adaptive hydrogel supports integrated osteochondral regeneration, including nearly continuous cartilage coverage, improved subchondral bone restoration, and superior local mechanical recovery. Overall, this work presents an enzyme-instructed self-strengthening strategy that couples an endogenous biochemical cue with β-sheet-rich secondary physical network formation, thereby providing a versatile stiffness-adaptive platform for stem cell regulation and graded osteochondral regeneration.
Zhang Z, Zhang F, Yang W
… +7 more, Xu J, Peng Z, Zhao X, Wei Y, Li G, Xie W, Wang X
Biomaterials
· 2026 Jun · PMID 42302584
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Pancreatic cancer has a dismal five-year survival rate of only ∼13%, owing to its insidious onset, rapid progression, and frequent primary or acquired resistance to gemcitabine (Gm). Moreover, intratumoral bacteria capab...Pancreatic cancer has a dismal five-year survival rate of only ∼13%, owing to its insidious onset, rapid progression, and frequent primary or acquired resistance to gemcitabine (Gm). Moreover, intratumoral bacteria capable of expressing cytidine deaminase (CDD) can undermine the therapeutic efficacy of Gm and contribute to chemoresistance. To address this challenge, antibiotic-drug conjugates (AiDCs, Tob-SS-Gm NPs) were developed by covalently linking tobramycin (Tob) and Gm via disulfide bonds. Tob-SS-Gm NPs retained antibacterial activity against E. coli and chemotherapeutic activity in Panc02 cells, indicating that the conjugation preserves the functional properties of both components. Meanwhile, disulfide linkage enables these AiDCs to remain stable under physiological conditions while undergoing cleavage in the high GSH tumor microenvironment, thereby releasing Tob and Gm for coordinated antibacterial and antitumor effects. In vivo evaluation demonstrated that Tob-SS-Gm NPs effectively reduced intratumoral bacterial burden and were associated with improved therapeutic response to Gm under bacteria-colonized tumor conditions. Furthermore, bacterial elimination and tumor cell damage were accompanied by modulation of the tumor immune microenvironment, including enhanced dendritic cell maturation and increased cytotoxic CD8 T-cell infiltration. Collectively, this AiDCs strategy provides a promising approach for the treatment of intratumoral bacteria-associated, drug-resistant malignancies.
Biomaterials
· 2026 Jun · PMID 42296789
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Osteoclasts are central effector cells in osteolytic diseases. Their differentiation and resorptive activity are regulated by stage-dependent cellular programs and by spatially and temporally changing pathological cues....Osteoclasts are central effector cells in osteolytic diseases. Their differentiation and resorptive activity are regulated by stage-dependent cellular programs and by spatially and temporally changing pathological cues. Aberrant osteoclast activation is therefore shaped by both cell-intrinsic signaling networks and extrinsic microenvironmental drivers. Recent advances in osteoclast-regulatory biomaterials include strategies that directly regulate osteoclast-lineage cells or modulate osteoclast-supportive microenvironments. In this review, we first summarize the biological basis of osteoclast overactivation and current clinical interventions. We then organize biomaterial strategies into a pathology-oriented framework covering direct regulation of osteoclast commitment, maturation, resorptive function and survival, and indirect regulation through osteoimmune, stromal, physicochemical and organ-bone axis-related mechanisms. Building on these biomaterial strategies and the clinical challenges of osteoclast-targeted intervention, we propose self-adaptiveness as an important future direction for osteoclast-regulatory biomaterials. Moreover, we also discuss emerging evaluation platforms that may strengthen the mechanistic assessment of stage-matched regulation, spatial localization, and remodeling compatibility. By linking biomaterials design to osteoclast biology and therapeutic requirements, this review provides a basis for future development of osteoclast-regulatory biomaterials with improved pathological adaptiveness.
Chen S, Li D, Zhou F
… +8 more, Huang Y, Zhang MJ, Xin L, Zhai Q, Chen T, Wan SC, Wang S, Song J
Biomaterials
· 2026 Jun · PMID 42296788
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Bacterial infections pose a major global health threat, with traditional antibiotics often failing due to drug resistance and recurrent infections. This study proposes a metal-phenolic therapeutic strategy that concurren...Bacterial infections pose a major global health threat, with traditional antibiotics often failing due to drug resistance and recurrent infections. This study proposes a metal-phenolic therapeutic strategy that concurrently targets bacterial cyclic di-adenosine monophosphate (c-di-AMP) synthase and leverages copper ion delivery to eradicate infections and prevent recurrence. Through structure-based virtual screening and in vitro validation, theaflavin 3,3'-digallate (TF3) was identified as a natural c-di-AMP synthase inhibitor, which was then integrated into a copper-based metal-phenolic network to yield TF3-Cu nanoparticles (TF3-Cu NPs). This system exhibits stimuli-responsive drug release in acidic biofilm microenvironments, synchronously inhibiting c-di-AMP synthesis and delivering copper ions. Transcriptomics analysis reveals that by disrupting c-di-AMP metabolism, TF3-Cu NPs impair bacterial cell wall/membrane functions, which induces intracellular copper accumulation. Intracellular copper overload disrupts the tricarboxylic acid cycle, triggering cuproptosis-like bacterial death while suppressing biofilm maturation. Notably, TF3-Cu NPs drive immunogenic bacterial death via cuproptosis, promote dendritic cell maturation and expands the memory B cell compartment, thereby conferring durable protection against Staphylococcus aureus reinfection. Overall, this study validates c-di-AMP synthase as a promising antibacterial target and establish a dual-mechanism, antibiotic-free material approach, which couples c-di-AMP pathway inhibition with bacterial cuproptosis induction to simultaneously suppress biofilms and potentiate host immunity.
Biomaterials
· 2026 Jun · PMID 42289163
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In situ cancer vaccination based on immunogenic cell death (ICD) represents a paradigm-shifting strategy in cancer immunotherapy, leveraging the tumor cells itself as an endogenous source of patient-specific antigens and...In situ cancer vaccination based on immunogenic cell death (ICD) represents a paradigm-shifting strategy in cancer immunotherapy, leveraging the tumor cells itself as an endogenous source of patient-specific antigens and damage-associated molecular patterns (DAMPs). This approach circumvents the need for exogenous antigen identification while minimizing off-target toxicities. Nanomedicine serves as a pivotal enabler in this paradigm by providing sophisticated spatiotemporal control over the critical stages of the antitumor immunity cycle. Specifically, nanodelivery systems are engineered to potentiate immunogenic antigen/DAMP release, including calreticulin (CRT), high-mobility group box 1 (HMGB1), and extracellular ATP, via precisely controlled chemo-, photo-, or radio-therapy. Furthermore, they amplify endogenous antigen processing and T cell priming through co-delivered molecular adjuvants, promote dendritic cell cross-presentation of tumor-derived antigens, and facilitate targeted delivery to lymph nodes. Concurrently, nanosystems remodel the immunosuppressive tumor microenvironment via the modulation of immunosuppressive immune cells, the blockade of immune checkpoints, and the interference with metabolic pathways. This review systematically examines recent advances in nanomedicine development centered on a trilogy of strategies for in situ induction of ICD, enhancement of antigen presentation and T cell activation, and remodeling the tumor immune microenvironment. We further critically analyze the key obstacles hindering clinical translation and offer forward-looking perspectives on future research directions. The integration of ICD inducers with advanced nanoplatforms represents a promising frontier for eliciting robust and systemic antitumor immunity.
Qian Y, Wang W, Xin M
… +8 more, Ding H, Shuai Y, Hu Z, Wang X, Huang S, Mu R, Zhang M, Jin L
Biomaterials
· 2026 Jun · PMID 42287984
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Radiotherapy for head and neck cancer frequently induces severe radiation-induced oral mucositis (RIOM), in which excessive reactive oxygen species (ROS), defective macrophage efferocytosis, and persistent inflammation f...Radiotherapy for head and neck cancer frequently induces severe radiation-induced oral mucositis (RIOM), in which excessive reactive oxygen species (ROS), defective macrophage efferocytosis, and persistent inflammation form a self-amplifying pathological loop that delays mucosal repair. Current symptomatic treatments are insufficient to simultaneously suppress oxidative stress and restore immune-mediated clearance of damaged cells. Here, we developed a detachable microneedle patch with ROS-responsive tips (PTC MN) for localized in situ macrophage programming within RIOM lesions. The PTC MN was fabricated from a PPBA-TA-PVA hydrogel matrix, which combines intrinsic ROS-scavenging capacity with oxidative stress triggered degradation, and loaded with engineered hybrid nanovesicles (HLENs-CAR) carrying a plasmid encoding CAR-ectoCRT-IL-4. This design enabled local delivery of gene-loaded nanovesicles, macrophage-targeted genetic programming, and sustained retention of the therapeutic payload in the injured mucosa. In a murine RIOM model, PTC MN accelerated mucosal epithelial regeneration, reduced oxidative stress and inflammatory infiltration, enhanced reparative macrophage responses, and attenuated fibrosis-associated tissue remodeling. Functionally, the platform enhanced macrophage efferocytosis, promoted IL-4-associated reparative polarization, and shifted the lesion microenvironment toward inflammation resolution and tissue regeneration. Collectively, this study establishes a smart in situ immunomodulation strategy that integrates ROS-responsive microneedle delivery with CAR-macrophage programming, providing a potential therapeutic paradigm for refractory mucosal injury.
Chen P, Zhao J, Yang JC
… +4 more, Su X, Zhang P, Feng HT, Tang BZ
Biomaterials
· 2026 Jun · PMID 42287983
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The management of superficial fungal infections is a major global public health burden, driving the need for precise and resistance-free therapies. While photodynamic therapy (PDT) mediated by photosensitizers (PSs) offe...The management of superficial fungal infections is a major global public health burden, driving the need for precise and resistance-free therapies. While photodynamic therapy (PDT) mediated by photosensitizers (PSs) offers a promising alternative, the lack of self-reporting capability in antifungal PSs hampers the accurate control of treatment and increases collateral risk from excessive reactive oxygen species (ROS). In this work, we designed and synthesized a series of aggregation-induced emission (AIE) PSs consisting of triphenylamine and 1H-indene-1,3(2H)-dione units, and found a versatile PS (named as ITTPM) that not only generates ROS efficiently but also simultaneously discriminates between live and dead fungi via a distinct fluorescence signal switch. In live fungi, ITTPM targets the cell membranes emitting red fluorescence. Upon fungal cell death, it relocates to the nuclei, staining them green. Mechanistic investigations via molecule imaging, lipid membrane mimicking experiment, DNA-responsive experiments and molecular docking revealed that ITTPM interacts with fungal membrane phospholipids via its aryl-substituted indanedione fragment and one pyridinium group in live fungi, versus binding to DNA bases via two cationic pyridinium fragments in dead cells. Furthermore, ITTPM shows potent photodynamic antifungal efficacy against planktonic fungi, effectively inhibits biofilm formation, and eradicates mature biofilms. In vivo studies on fungi-infected mouse wounds demonstrated that ITTPM achieved complete fungal eradication, facilitated wound healing and exhibited excellent biocompatibility. This study provides a promising candidate PS for precise clinical treatment of superficial fungal infections and novel insights into developing multifunctional antifungal PSs.
Wang Y, Cao J, Wang X
… +7 more, Liu T, Jiang H, Jiang J, Wang Y, Yuan H, Wu S, Wu F
Biomaterials
· 2026 Jun · PMID 42275848
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The regeneration of aged bone is severely compromised by a deteriorating microenvironment characterized by excessive reactive oxygen species (ROS) and consequential endoplasmic reticulum stress (ERS). Herein, we report a...The regeneration of aged bone is severely compromised by a deteriorating microenvironment characterized by excessive reactive oxygen species (ROS) and consequential endoplasmic reticulum stress (ERS). Herein, we report a biomimetic nanozyme engineered through synergistic p-d orbital hybridization and youthful membrane camouflage to precisely reverse this degenerative cascade. The designed Cu-Sn dual-atom core exhibits exceptional multi-enzymatic activity, scavenging superoxide anions with a 2.5-fold higher efficiency than Cu single-atom control. Mechanistic studies confirm that p-d hybridization redistributes electron density at the Sn site, lowering the energy barrier for ROS adsorption and conversion. This catalytic core is cloaked with a hybrid membrane derived from young mesenchymal stem and endothelial cells, which facilitates targeted delivery to senescent bone niches and provides intrinsic pro-regenerative signals. The composite nanozyme effectively mitigates intracellular oxidative stress and ERS in aged cells, rescuing their osteogenic and angiogenic potential. In an aged mouse model of jawbone defect, a single treatment regimen promoted robust bone regeneration, increasing the bone volume fraction (BV/TV) by 1.7-fold and significantly enhancing new bone mineralization. This work establishes a dual-principle design-orbital hybridization for catalytic amplification and youthful membrane for targeted rejuvenation-offering a versatile platform for treating a spectrum of senescence-associated diseases.
Dhawan V, Narayanan S, Thompson C
… +4 more, Shi D, Patel Y, McClung CA, Cui XT
Biomaterials
· 2026 Jun · PMID 42275847
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Chronically implanted neural electrodes for neural recording, stimulation, and chemical sensing are essential tools in studying and treating neurological disorders. However, their performances are limited by implant-indu...Chronically implanted neural electrodes for neural recording, stimulation, and chemical sensing are essential tools in studying and treating neurological disorders. However, their performances are limited by implant-induced inflammation, causing a loss in signal quality over time. Because disease states can alter inflammatory processes, it is critical to characterize the tissue response to neural implants within relevant disease models. Circadian rhythm disruption is a hallmark of many psychiatric and neurodegenerative disorders, yet its influence on neural implant performance remains poorly understood. The Circadian Locomotor Output Cycles Kaput (Clock) gene is a core regulator of circadian rhythms and a key modulator of inflammatory pathways, including NF-κB signaling. The ClockΔ19 mutant mouse is a well-established model of circadian disruption with documented immunological abnormalities. Here, we evaluated striatal electrophysiological recording performance and quantified the host tissue response to microelectrode implants in ClockΔ19 (MU) and wild-type (WT) mice over four weeks. Silicon microelectrode arrays (MEAs) were implanted into the striatum, followed by weekly electrochemical impedance spectroscopy and neuronal recording measurements. Electrodes implanted in MU mice exhibited significantly lower impedance, noise, and peak-to-peak amplitude compared to WT mice, while signal-to-noise ratio and channel yield were comparable between groups. Endpoint immunohistological analyses revealed significantly reduced microglia and astrocyte activity, as indicated by lower Iba-1 and GFAP intensities around the implant site in MU mice. Additionally, ClockΔ19 tissue showed elevated 4- hydroxynonenal (HNE) levels and reduced nuclear NF-κB expression following implantation. Morphological analysis further identified baseline and injury-induced differences in microglia phenotypes between MU and WT animals. Notably, decreased neurofilament expression, together with a non-significant trend toward reduced neuronal density, suggests compromised neuronal health surrounding the implant in MU animals. Together, these findings demonstrate that circadian disruption alters both neural and immune responses to chronic neural implants, resulting in heightened oxidative stress and an impaired reparative inflammatory response. This work highlights the importance of circadian regulation in neuroimmune responses, providing insights into how circadian dysfunction may impact long-term neural interface performance with implications for both basic research and clinical neurotechnology development.
Gao D, Wang H, Liu C
… +5 more, Ni J, Wang G, Yao H, Wan X, Zheng D
Biomaterials
· 2026 Jun · PMID 42269443
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Urethral stricture, a fibrotic condition causing lumen narrowing, lacks effective pharmacological treatments, with autologous grafts facing donor-site limitations. Tissue engineering strategies, particularly anisotropic...Urethral stricture, a fibrotic condition causing lumen narrowing, lacks effective pharmacological treatments, with autologous grafts facing donor-site limitations. Tissue engineering strategies, particularly anisotropic hydrogels, offer promising alternatives but remain unexplored in urethral repair. Here, we developed a multifunctional anisotropic polyvinyl alcohol/tannic acid (APVA/TA) hydrogel via mechanical training and hydrogen-bond crosslinking for urethral reconstruction. The APVA/TA hydrogel exhibited enhanced crystallinity, mechanical strength, and anti-swelling properties, with TA conferring potent antioxidant and broad-spectrum antibacterial activity. In vitro, TA suppressed LPS-induced inflammatory responses, while the anisotropic structure synergistically promoted endothelial cell migration and angiogenesis. In a rabbit urethral stricture model, the APVA/TA2.5 hydrogel significantly reduced stricture recurrence (12.6% obstruction rate) and facilitated improved repair through enhanced epithelial regeneration (pan-CK), vascularization (CD31), and smooth muscle regeneration (α-SMA). This study demonstrates the dual role of anisotropic structure and TA in enabling functional urethral reconstruction, providing a novel tissue-engineered solution for stricture management.
Liu X, Liu Z, Li H
… +8 more, He Y, Shu T, Li J, Wang Y, Song Y, Zhang J, Tan H, Li J
Biomaterials
· 2026 May · PMID 42263650
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Engineered bacterial therapeutics have shown promising performance in treating various chronic and inflammatory diseases. However, inadequate colonization of therapeutic bacteria at disease sites, which usually impairs e...Engineered bacterial therapeutics have shown promising performance in treating various chronic and inflammatory diseases. However, inadequate colonization of therapeutic bacteria at disease sites, which usually impairs efficacy, remains a critical challenge that needs to be addressed for clinical translation of live biotherapeutics. Herein, we report an innovative approach to enhance the colonization of probiotic Escherichia coli Nissle 1917 (EcN) by genetically replacing its native capsular polysaccharide with hyaluronan, a human glycosaminoglycan that potentiates bacterial stress tolerance, mucoadhesion, and phagocytosis resistance. Using hyaluronan-mediated colonization, the engineered EcN strain expressing recombinant superoxide dismutase (SOD) further exhibited a significantly improved efficacy against dextran sulfate sodium (DSS)-induced colitis in mice, as demonstrated by the remarkable resolution of ulcerative colitis following a single administration. Collectively, hyaluronan-based capsular polysaccharide engineering represents a robust platform to improve bacterial colonization, thus developing effective therapeutic bacteria targeting ulcerative colitis or other bowel diseases.
Lai H, Li G, Guo K
… +4 more, Zhang H, Li S, Yang F, Chen T
Biomaterials
· 2026 Jun · PMID 42263649
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Metabolic rewiring-induced immune dysfunction limits the efficacy of NK cell-based immunotherapy for solid tumors, underscoring the need for targeted metabolic interventions. In this study, we found that NK cells within...Metabolic rewiring-induced immune dysfunction limits the efficacy of NK cell-based immunotherapy for solid tumors, underscoring the need for targeted metabolic interventions. In this study, we found that NK cells within tumor tissues exhibited lipid accumulation and decreased infiltration across multiple tumor models, including B16F10 melanoma, MC38 colon carcinoma, 4T1 breast cancer, and LLC lung carcinoma. Among the selected common selenium species, including Selenocystine (SeCys), selenomethionine (SeMet) and selenium nanoparticles (SeNPs), SeNPs were found to effectively reverse abnormal lipid metabolism-mediated NK cell immune exhaustion induced by palmitic acid, oleic acid, or tumor-conditioned media. Additionally, SeNPs also effectively reverse palmitic acid-induced diminished antitumor activities in NK cells in vivo. Mechanistically, SeNPs inhibited palmitoylation of the fatty acid transporter CD36, restricting membrane localization and excessive lipid uptake, thereby preventing PPARδ-mediated mTOR inactivation and mitochondrial dysfunction. Importantly, SeNPs maintained glutathione peroxidase 1 (GPX1) protein abundance by counteracting palmitoylation-dependent downregulation, preserving redox homeostasis and sustaining mTOR signaling to enhance NK cell immunity. Furthermore, we also found that there is a positive correlation between high GPX1 expression and tumor-infiltrating NK cells in human breast tumor tissues, which further highlights the importance of elevated GPX1 expression in NK cell-mediated antitumor activity. Taken together, this study identifies SeNPs as a metabolic regulator that reprograms dysregulated lipid metabolism to restore NK cell antitumor immunity, which provides a mechanistic framework for developing selenium-based metabolic strategies to enhance cancer immunotherapy.
Zang Q, Qin Z, Ou J
… +14 more, Wang M, Zhou L, Zhou J, Yang X, Shen R, Wang K, Luo Y, Wu H, Mou J, Wu J, Cai X, Du W, Zheng Y, Li Y
Biomaterials
· 2026 Jun · PMID 42258904
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Copper (Cu) homeostasis dysregulation is one of the key factor exacerbating mitochondrial dysfunction and impairing cardiac repair in myocardial infarction (MI). Herein, by integrating single-cell transcriptomics, clinic...Copper (Cu) homeostasis dysregulation is one of the key factor exacerbating mitochondrial dysfunction and impairing cardiac repair in myocardial infarction (MI). Herein, by integrating single-cell transcriptomics, clinical specimens, and animal models, we first identified negative regulator of Cu homeostasis MI. We then constructed a Cu nanoregulator, Qu@Cu-SS31, that selectively accumulate in the mitochondria of ischemic cardiomyocytes and release bioactive Cu in a pH-responsive manner, enhancing mitochondrial function and promoting myocardial recovery. Mechanistic studies revealed that Qu@Cu-SS31 mediated significant downregulation of COMMD1, concomitant with downregulation of Cu transporters CTR1 and CCS. Additionally, Qu@Cu-SS31 showed robust reactive oxygen species scavenging ability. This COMMD1-Cu-ROS regulatory axis potently inhibited NLRP3-Caspase-1 dependent pyroptosis, and apoptosis via rebalance of Bcl-2/Bax expression. In a mice MI model, Qu@Cu-SS31 exhibited preferential accumulation in infarcted regions, leading to significant functional recovery, reduced infarct size, and enhanced tissue regeneration. Our work establishes a novel nanoregulator for Cu homeostasis restoration and illustrates the critical role of COMMD1 downregulation in mitigating mitochondrial damage, highlighting the therapeutic potential of Cu homeostasis regulation in cardiovascular applications.