Wiley: Advanced Science: Table of Contents

Mesenchymal Stromal Cell‐Mediated Intercellular Communication: Mapping the Interactome for Skeletal Muscle Homeostasis and Regeneration

Fri, 29 May 2026 00:42:31 -0700

Liu et al. define a systems-level interactome of fibroadipogenic progenitor (FAP)-mediated signaling in skeletal muscle by integrating single-cell transcriptomics with FAP depletion-based perturbation analysis. Functional interrogation using a conditioned media bioassay links predicted signaling to multicellular outcomes, establishing a framework to decode stromal regulation of tissue homeostasis and regeneration.

ABSTRACT

Mesenchymal stromal cells (MSCs) support tissue homeostasis and regeneration, yet their molecular signals remain largely enigmatic. In skeletal muscle (SkM), MSCs, known as fibroadipogenic progenitors (FAPs), are essential for maintenance and repair, orchestrating these processes through intricate cellular communication networks. Given the critical role of SkM in lifelong health and longevity, FAP signaling has drawn significant interest as a potential therapeutic target and a model for MSC interactions. However, deciphering FAP-derived regulatory signals remains challenging due to their pleiotropic complexity. Here, we employ a systems-level approach to construct a comprehensive FAP interactome in both homeostatic and regenerating SkM. By integrating unique single-cell RNA sequencing atlases with advanced computational analyses, we identify putative FAP-mediated signaling pathways and validate their biological relevance through FAP depletion experiments, assessing disruptions in key pathways. This approach reveals novel signaling networks across diverse SkM cell populations, corroborates key FAP interactions from recent studies, and provides a valuable dataset for modeling MSC interactions and their roles in SkM homeostasis and regeneration.

Machine Learning‐Driven Prediction of Microplastic Aging Processes and Environmental Risk Assessment Across Multi‐Media Systems

Thu, 28 May 2026 06:31:12 -0700

This perspective proposes a cohesive machine learning strategy to decode microplastic aging. It advocates for Federated Learning to dismantle global data silos and introduces the TRACE framework (TRansport, Aging, Corona, Ecotoxicity). By integrating physics-informed modeling with causal discovery, this approach bridges the laboratory-field gap to enable mechanistic, predictive environmental risk assessment.

ABSTRACT

Machine learning (ML) holds promise for reconstructing microplastic (MP) aging and assessing risks, but current studies rely on small-scale, accelerated laboratory datasets and single environmental medium models that miss cross-media transport and environmental interactions in real-world MP lifecycles. To realize its potential for reconstructing spatiotemporal aging trajectories and toxicological assessment of MPs, this perspective provides a paradigm shift in ML application from fragmented data-fitting to a holistic, privacy-preserving, physics-aware strategy. A novel probabilistic framework reconstructs the environmental history of field-sampled MPs through mechanistic fingerprinting, using Bayesian inference to reconcile multi-evidence signals and improve trajectory models for source attribution and risk assessment. Furthermore, we propose the TRACE framework (TRansport, Aging, Corona, Ecotoxicity), which moves beyond the isolated modeling of aging processes and toxicity endpoints. By integrating physics-informed models with causal discovery, TRACE captures the reciprocal feedback loops between physicochemical evolution and eco-corona formation, thereby mechanistically linking surface transformations to biological risks. To support this data-intensive architecture, we advocate for federated learning (FL) to dismantle privacy barriers. This approach facilitates secure, multi-institutional collaborative modeling without raw data exchange, harmonizing heterogeneous datasets. Ultimately, this cohesive strategy bridges laboratory-field disparities, moving toward predictive, evidence-based, and targeted mitigation efforts in global plastic pollution governance.

Restriction of Individual Branched‐Chain Amino Acids has Distinct Effects on the Development and Progression of Alzheimer's Disease in 3xTg Mice

Thu, 28 May 2026 01:37:16 -0700

Protein restriction (PR) slows Alzheimer's disease (AD) in mice, and other benefits of PR are due to decreased branched-chain amino acids (BCAAs). We show that restricting any BCAA has benefits, with sex- and BCAA-specific impacts on pathology, molecular signaling, and cognition. These findings highlight dietary composition as critical in the development and progression of AD, and could guide future therapies.

ABSTRACT

Dietary protein regulates metabolic health and aging, with many benefits of a low protein diet resulting from reduced consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Each BCAA has distinct physiological and molecular effects, and while restriction of protein or all three BCAAs improves cognition in mouse models of Alzheimer's disease (AD), the role of each individual BCAA on AD is unknown. Here, we investigate the impact of restricting leucine, isoleucine, or valine on metabolism, AD pathology, molecular signaling, and cognition in male and female 3xTg AD mice. Mice were fed BCAA-restricted diets for nine months starting at six months of age. Restriction of either isoleucine or valine, but not leucine, improved metabolic health. We observed distinct, BCAA-specific effects on AD pathology, molecular signaling, and gene expression in both sexes as well as shared molecular responses in males. Restricting any BCAA improved short-term memory in males, with isoleucine having the strongest effect, while valine restriction led to the greatest cognitive benefits for females. These findings suggest that targeted BCAA restriction, particularly of isoleucine or valine, may form the basis of a novel sex-specific approach to prevent or delay AD.

Senomorphic Small Extracellular Vesicles Delivered by a Tissue‐Adhesive α‐Lipoic‐Acid Hydrogel Enable Immuno‐Rejuvenation for Bone‐Tendon Interface Regeneration

Thu, 28 May 2026 01:37:16 -0700

This work identifies M1 macrophage-mediated inflammation as a key driver of BMSC senescence and bone microstructural deterioration at the enthesis. A tissue-adhesive hydrogel delivering senomorphic small extracellular vesicles suppresses this inflammatory-senescent cascade and enhances BMSC resilience by inhibiting the cGAS-STING-NF-κB pathway. In an osteoporotic rat model, this dual immunomodulatory and senomorphic strategy accelerates bone-tendon interface regeneration.

ABSTRACT

Chronic inflammation-driven bone loss in aging compromises bone regeneration and further impairs the bone-tendon interface (BTI). However, the cellular mechanisms by which inflammation exacerbates cellular senescence and consequently disrupts BTI healing remain unclear. Here, we identify M1 macrophage-mediated inflammation as a key driver of bone marrow-derived mesenchymal stem cells (BMSCs) senescence and bone microstructural deterioration. This senescence-associated decline in BMSCs ultimately compromises osteogenesis and delays BTI repair. To counteract these effects, we engineered a senomorphic and immunomodulatory platform by incorporating quercetin-primed senomorphic small extracellular vesicles (Sm-sEV) into a tissue-adhesive α-lipoic acid hydrogel (αLA-Gel) for sustained local delivery. The composite material modulates the inflammatory-senescent microenvironment by attenuating M1 macrophage-driven inflammation and enhancing BMSC resilience to inflammation-exacerbated senescence. Mechanistic analyses revealed that Sm-sEV/αLA-Gel suppresses cGAS-STING-NF-κB signaling, thereby reducing inflammation and improving BMSC resistance to senescence. In an osteoporotic rat rotator cuff repair model, Sm-sEV/αLA-Gel enhanced bone formation and fibrocartilage maturation, thereby promoting superior BTI integration and mechanical strength. Together, these findings identify inflammation-exacerbated BMSC senescence as a key pathological driver and demonstrate that dual regulation of inflammation and stem cell resilience enables robust regeneration of bone and the BTI under osteoporotic conditions.

tBid‐Mediated Genetic Ablation of Connective Tissue Cells Reveals Their Key Regulatory Function During Limb Regeneration in Axolotls

Wed, 27 May 2026 08:05:24 -0700

We establish a tBid-mediated cell ablation system in axolotls, achieve rapid and efficient ablation of multiple cell types, including muscle stem cell, spinal cord cell, and connective tissue (CT) cells. We investigate the role of CT using tBid-mediated CT ablation and identify its essential role for limb development and regeneration.

ABSTRACT

Vertebrate limb regeneration in adulthood is a fascinating phenomenon unique to salamanders, requiring precise coordination and interaction of various cell types. Connective tissue (CT) constitutes a major component of the limb and serves as the primary reservoir of positional information during regeneration. However, the role and extent of CT cell contribution remain largely undefined. Here we develop an inducible Cre-LoxP-mediated tBid cell ablation system in axolotls and demonstrate efficient elimination of targeted muscle tissue and muscle stem cells through transient electroporation or genetic approach. Ablation of CT cells at early regeneration stages results in delayed regeneration and loss of proximal limb segments (e.g., upper and lower limb), with minimal impact on hand differentiation. CT ablation during development yields similar defects, supporting an essential role for CT cells in determining the positional identity of developing and regenerating limb structures. Further single-cell RNA-sequencing (scRNA-seq) reveals a progressive proximal-to-distal transition among CT cells and identifies distinct CT subtypes contributing to proximal and distal segments. CT ablation reduces differentiated CT1—a subpopulation maintaining proximal identity throughout regeneration, and delays distal transformation in proliferative CT1 progenitors. These cellular shifts likely explain the observed morphological deficits. Moreover, differentiated CT1 cells enhance interactions with surrounding cells after CT ablation to modulate adaptive proliferation in other populations (e.g., muscle stem cells). Our work establishes a tBid-based ablation strategy for functional studies of CT and other cell types in axolotls and demonstrates pivotal roles of CT cells in limb regeneration.

Pathological Mechanism‐Inspired Biomimetic Nano‐Senotherapy for Reversing Experimental Atherosclerosis in ApoE−/− Mice

Mon, 25 May 2026 07:49:44 -0700

The biomimetic self-assembly nanomedicine reversing atherosclerosis via senotherapy strategy.

ABSTRACT

The greatest challenge in atherosclerosis (AS) management lies in achieving lesion reversal, not merely slowing progression. Senescent cell accumulation—driven by continuous generation and apoptotic resistance—perpetuates plaque pathology and obstructs regression. This study addresses the reversal conundrum through a dual-action strategy: blocking new senescent cell formation while enhancing clearance of existing senescent cells. We developed a ROS-responsive dimeric prodrug (K₂A) from the MPO-inhibitory tripeptide KYC, which co-assembles with the senolytics Navitoclax into a nano-Senotherapy (N@K₂A). Further cloaked with neutrophil membranes from AS mice, the biomimetic N@K₂A@NEM precisely targets plaques, responds to local ROS, and orchestrates senescent cell formation and removal. This targeted senotherapeutic intervention demonstrates effective reversal of established experimental AS, offering a potential solution to the field's most pressing clinical dilemma.

Neuid: A Novel Neuron‐Enriched LncRNA that Connects Epigenetic Gene Silencing to Alzheimer's Disease

Fri, 22 May 2026 01:13:49 -0700

ABSTRACT

The increasing evidence that non-coding RNAs can become deregulated during pathogenesis is dramatically expanding the space for drug discovery beyond the protein-coding genome. Long noncoding RNAs (lncRNAs) are emerging as key regulators of cellular function, yet most remain uncharacterized. Here, we identify a previously unstudied lncRNA, which we named Neuronal Identity (Neuid), a conserved, brain-enriched transcript expressed in neurons. Neuid is downregulated in the brains of Alzheimer's disease (AD) patients. Mechanistically, Neuid maintains neuronal identity by repressing developmental and glial genes via interaction with the PRC2 subunit EZH2 and regulation of H3K27me3. Knockdown of Neuid disrupts this repression, leading to impaired neuronal activity and memory formation. Importantly, CRISPRa-mediated Neuid overexpression restores neuronal function in Aβ42-treated neurons. These findings identify NeuID as a critical regulator of neuronal plasticity and position it as a promising therapeutic target for AD

Nicotinamide and Pyridoxine Supplementation Enhances Muscle Stem Cell Activity and Muscle Regeneration in Humans: A Randomized Placebo‐Controlled Clinical Trial of High Force Eccentric Contraction Recovery in Healthy Young Men (Adv. Sci. 28/2026)

Mon, 18 May 2026 00:00:00 -0700

Human Muscle Regeneration

This frontispiece shows regenerating human skeletal muscle stained for embryonic myosin heavy chain (eMyHC) eight days after high intensity contraction and daily Nicotinamide and Pyridoxine supplementation. eMyHC-positive fibers mark newly formed myofibers arising from activated muscle stem cells. Nicotinamide and pyridoxine supplementation enhances this regenerative process by promoting muscle stem cell proliferation, differentiation, and progression toward muscle repair. More details can be found in the Research Article by Jerome N. Feige, Pascal Stuelsatz, Abigail L. Mackey, and co-workers (DOI: 10.1002/advs.202518471).

Nicotinamide and Pyridoxine Supplementation Enhances Muscle Stem Cell Activity and Muscle Regeneration in Humans: A Randomized Placebo‐Controlled Clinical Trial of High Force Eccentric Contraction Recovery in Healthy Young Men

Mon, 18 May 2026 00:00:00 -0700

In a randomized clinical trial, we test the potential of combined nicotinamide (NAM) and pyridoxine (PN) to improve muscle recovery through muscle stem cell (MuSC) activity. Daily oral NAM and PN supplementation after high intensity muscle contractions enhances MuSC activation and differentiation, and accelerates muscle regeneration, providing new opportunities for therapeutic applications in muscle recovery and muscle wasting disorders.

ABSTRACT

Muscle Stem Cells (MuSCs) drive muscle regeneration and slow pathological progression of muscle diseases. In preclinical models, nicotinamide (NAM) and pyridoxine (PN) synergistically increased MuSC proliferation and differentiation, and accelerated muscle regeneration. Herein we tested if NAM/PN could enhance MuSC activity and muscle regeneration in a randomized, placebo-controlled clinical trial. Men aged 18–49 years were supplemented daily with 714 mg NAM and 19 mg PN, or placebo, for 9 days following one session of damaging unilateral eccentric muscle contractions. The primary endpoint was MuSC activity via immunohistofluorescence on biopsy sections from the vastus lateralis muscle. Histological markers of muscle regeneration constituted secondary outcomes, and muscle damage was validated with clinical markers. 39 out of 43 enrolled participants completed the study. Supplementation of NAM/PN was well tolerated and increased blood concentrations of NAM and PN vitamers. 8 days after the contraction protocol, the number of Pax7, MyoD, and myogenin positive cells per damaged fiber was significantly higher in NAM/PN vs placebo groups (+29%–67%). NAM/PN also increased the proportion of regenerating fibers (+37%). Daily oral NAM/PN supplementation after high intensity muscle contractions enhances MuSC activity and accelerates muscle regeneration and repair, providing new opportunities for therapeutic applications in muscle recovery and muscle wasting disorders.

Development‐based In Vivo Bioreactor Strategy for Challenging Senescent Bone Reconstruction

Mon, 18 May 2026 00:00:00 -0700

We present a development-based in vivo bioreactor strategy to generate rejuvenated bone grafts (vBR-Bone) within aged hosts. By enclosing vBR-Bone fragments within an asymmetric biomimetic periosteum, segmental femoral defects in aged mice were successfully repaired within 6 weeks. Mechanistically, the multifactors of vBR-Bone reconstitute a remodeling microenvironment, wherein matrix-released TGF-β1 activates the PI3K/AKT/mTOR signaling axis via TRAF6-dependent ubiquitylation. This mechanism promotes robust osteogenesis and integration, thereby overcoming senescence-associated healing compromises.

ABSTRACT

Critical segmental bone defects in elderly patients pose a formidable clinical challenge due to limited autograft availability, senescent bone dysfunction, and compromised healing from fibrous tissue invasion. Here, we present a development-based in vivo bioreactor strategy wherein BMP-2-loaded biomaterials trigger the body's intrinsic developmental programs, using the organism as a bioreactor to engineer bone. Distinct from classical developmental engineering, this in vivo bioreactor-derived bone (vBR-Bone) recapitulates native osseous architecture, including vasculature, cortical bone, trabeculae, and bone marrow niche. In aged murine models, the vBR-Bone exhibits a rejuvenated restoration of bone bioactivity lost in aging, with reduced senescence, elevated remodeling, and improved stem cell functionality. Capitalizing on its restored remodeling capacity of high bone turnover, the vBR-Bone fragments enclosed in an asymmetric biomimetic periosteum achieved 6-week repair of critical-sized 1/3 femoral shaft segmental defects. Through a “compartmentalized” approach that partitions the defect into manageable fragments, vBR-Bone progressively remodeled and integrated into functional trabecular bone, ultimately restoring bone mineral density, volume, and microstructure in defects of aged mice. The biomimetic periosteum inhibits fibrous invasion while permitting vascular ingrowth, thereby creating a space for regeneration. Mechanistically, the multifactors within vBR-Bone reconstitute a bone-remodeling microenvironment, wherein matrix-released TGF-β1 activates the PI3K/AKT/mTOR signaling axis via TRAF6-dependent ubiquitylation to promote robust osteogenesis. This strategy overcomes autograft shortage and senescence-associated dysfunction, offering a clinically translatable solution for critical age-related segmental bone defects.

18β‐Glycyrrhetinic Acid and a Nano‐Liposomal Formulation Alleviate Depression‐Like Behaviors via the Microglial mTOR‐Autophagy‐NLRP3 Axis

Mon, 18 May 2026 00:00:00 -0700

Using a novel zebrafish-based inflammatory screening strategy, we screened and identified 18β-glycyrrhetinic acid (18β-GA) as a promising anti-inflammatory candidate. We uncover a microglial mTOR–autophagy–NLRP3 axis that constitutes the mechanistic core of 18β-GA–mediated neuroprotection. An engineered nanoliposomal 18β-GA achieves rapid antidepressant efficacy after a single dose, with favorable biosafety and translational potential.

ABSTRACT

The limited efficacy and slow onset of current antidepressants underscore the urgent need for novel therapeutic strategies. Here, we established a novel zebrafish inflammation-based screening model and identified 18β-glycyrrhetinic acid (18β-GA) as a potent anti-inflammatory candidate. In a chronic social defeat stress (CSDS) mouse model, 18β-GA demonstrated significant antidepressant effects, which were associated with attenuated neuroinflammation and a shift in microglial polarization toward an anti-inflammatory phenotype. Mechanistically, 18β-GA inhibited the mTOR/p70S6K signaling pathway, leading to the restoration of autophagy and subsequent suppression of NLRP3 inflammasome activation in microglia. Using a transwell co-culture system, we further confirmed that 18β-GA protects neurons from microglia-mediated inflammatory injury. To overcome pharmacokinetic limitations, we developed a nanoliposomal formulation (Nano 18β-GA) that achieved rapid brain accumulation within 0.5 h, as visualized by time-dependent in vivo imaging. Remarkably, a single administration of Nano 18β-GA produced significant antidepressant effects, maintained the original mechanism of action, and exhibited a favorable biosafety profile. Together, our work delineates a translational pipeline from natural product discovery to nano-enabled therapy, offering a rapidly acting strategy with substantial translational potential for depressive disorder.

Alzheimer's Disease Risk Factor APOE4 Exerts Dimorphic Effects on Female Bone

Mon, 18 May 2026 00:00:00 -0700

In aging bone, osteocytes accumulate neurodegenerative risk factor Apolipoprotein E (APOE). A humanized version of the Alzheimer's disease risk allele APOE4 altered the mouse bone transcriptome and proteome, with effects in female bone surpassing the brain, including bone fragility due to suppressed osteocytic maintenance of bone quality, identifying APOE as a novel age-related risk factor linking skeletal and neurologic health.

ABSTRACT

Individuals with Alzheimer's disease (AD) are at an increased risk of bone fracture, while osteoporosis in women is one of the earliest predictors of AD. Yet the mechanisms linking cognitive decline and skeletal deterioration remain poorly defined. Proteomic analysis of cortical bone from aged 21-month-old mice revealed strong enrichment of neurodegeneration-associated proteins, including apolipoprotein E (Apoe) and amyloid precursor protein. Apoe localized specifically to osteocytes, with expression in aged female bone nearly twice that of young 4-month-old male bone. Because human APOE alleles confer different age-related AD risks, we examined their roles in bone using humanized APOE2, APOE3, and APOE4 knock-in mice and analyzed bone and hippocampus from the same animals. APOE4 produced marked sex-specific effects on the bone transcriptome and proteome compared with APOE2 or APOE3. Strikingly, APOE4-associated proteomic disruptions were stronger in female bone than in the hippocampus. Functionally, APOE4 caused bone fragility in females without altering cortical structure. These deficits stemmed from impaired osteocyte perilacunocanalicular remodeling. Our findings identify APOE4 as a molecular driver of early osteocyte dysfunction and reduced bone quality, disproportionately affecting females. These findings highlight osteocytes as potential targets for early diagnosis of age-related cognitive impairment and treatment for bone fragility, in females.

Reply to the Comments on “GLM7—A Novel Composite Glycolipid Index Derived from Routine Health Indicators for Enhanced Diagnosis and Prediction of Multimorbidity”

Zhihua Wang, Suowen Xu — Wed, 13 May 2026 00:30:13 -0700

ABSTRACT

This paper is a formal response to the comments raised by Yiquan Wang et al. and Peikai Sun et al. on our published work entitled “GLM7–A Novel Composite Glycolipid Index Derived from Routine Health Indicators for Enhanced Diagnosis and Prediction of Multimorbidity”. We address all the comments in this response. In addition, we emphasize the intended application scenarios and potential limitations of GLM7 and discuss future research efforts to improve its methodological rigor and interpretability.

Distinct Immunomodulatory Strategies Guide Mesenchymal Stromal/Stem Cell‐Mediated Bone Regeneration

Wed, 13 May 2026 00:30:13 -0700

Bone regeneration by mesenchymal stem cells is strongly influenced by immune signals. This study shows that priming stem cells with regulatory immune cells or an inflammation-resolving lipid molecule enhances bone formation through distinct immune pathways. The findings highlight how tailored immune modulation can direct stem cell fate and improve regenerative outcomes.

ABSTRACT

The bone regenerative potential of bone marrow-derived mesenchymal stromal/stem cells (MSC) is critically shaped by their interaction with the host immune system. Here, we compare two MSC priming strategies: coculture with regulatory T cell (Treg) or exposure to the proresolving mediator Resolvin E1 (RvE1) to enhance ectopic osteogenesis in mice. Both approaches enhance MSC-mediated bone formation through distinct local and systemic immunomodulatory mechanisms. Treg priming promotes a regulated anti-inflammatory environment characterized by reduced IL-6 protein levels (3.6-fold), sustained IL-13 elevation up to 10 weeks (1.5-fold compared with RvE1), early suppression of cytotoxic CD8⁺ T cells and IFN-γ production by CD4⁺ T cells in lymph nodes, a >25% reduction in fibrous capsule formation, and enhanced B cell activity, collectively supporting ossification. In contrast, RvE1 priming promotes early TNF-α and late granulocyte-macrophage colony-stimulating factor (GM-CSF) production (1.2-fold compared with Treg) within the scaffold, facilitating osteoblast maturation. Transcriptomic profiling revealed distinct osteogenic signatures, with amphiregulin uniquely upregulated in the Treg group (>7-fold). Using a Treg depletion model, we further demonstrate that RvE1 retains partial immunomodulatory capacity and supports matrix organization. Together, these findings underscore the versatility of immune modulation in directing MSC fate and highlight the potential of tailoring immunoregulatory strategies to optimize bone regeneration.

A NeuroD1 AAV‐Based Gene Therapy for Functional Brain Repair in Alzheimer's Disease‐Like Non‐Human Primate Model

Wed, 13 May 2026 00:30:13 -0700

This study tests NeuroD1 AAV-based gene therapy in a non-human primate Alzheimer's disease model. The therapy prevents neuronal damage, inhibits hippocampal atrophy, and reduces neuroinflammation. It also repairs vascular and blood-brain barrier damage, restores cerebrospinal fluid biomarkers, enhances hippocampal glucose metabolism, and improves spatial memory. Transcriptome analysis reveals enhanced neuronal function and reduced neuroinflammation, supporting its therapeutic potential.

ABSTRACT

There is a pressing demand for neuroregenerative treatment for Alzheimer's disease (AD). Recently, a NeuroD1-mediated neuroregeneration strategy has been proposed, yet its efficacy remains untested in non-human primate (NHP) AD models closely reflecting human pathology. This study evaluates the therapeutic potential of NeuroD1 AAV-based gene therapy in an NHP AD model with hippocampal hTau overexpression, utilizing immunostaining, fluorescence/confocal imaging, MRI and FDG PET scans, Simoa CSF biomarker analysis, behavioral tests, and bulk RNA sequencing. NeuroD1 AAV-based gene therapy prevents neuronal damage and degeneration, inhibits hippocampal atrophy, and reduces neuroinflammation in NHP AD models. It also repairs vascular and BBB damage, restores CSF AD biomarker levels, improves hippocampal glucose metabolism, and enhances spatial working memory. Transcriptome analysis further reveals upregulated neuronal function and synaptic transmission, along with downregulated neuroinflammation and apoptosis. Collectively, our findings demonstrate that NeuroD1 AAV-based gene therapy repairs and restores brain structure and function in NHP AD models, highlighting its therapeutic potential.

Nanoplastics and Neurodegeneration: A Roadmap From Mechanism to Causation

Yuhuan Li, Yue Wang, Xiufang Liang, Mengze Xu, David T. Leong, Pu Chun Ke — Wed, 13 May 2026 00:30:13 -0700

Nanoplastics are pervasive environmental contaminants with potentially profound implications for human health. Emerging evidence suggests a possible link between nanoplastic exposure and neurodegeneration, a key driver of ageing and dementia, yet causality remains unresolved. This Perspective synthesizes current evidence, identifies critical knowledge gaps and deficiencies, and outlines a multidisciplinary roadmap to clarify causal links and guide safer materials innovation.

ABSTRACT

Nanoplastics are ubiquitous by-products of global plastic production and have emerged as a potentially consequential yet insufficiently defined threat to health. Recent studies have revealed that these synthetic particulates can cross the blood-brain barrier, accelerate amyloid aggregation, impair microglial clearance, hijack the gut-liver-brain axis, and drive neuroinflammation—mechanisms central to neurodegeneration in Alzheimer's and Parkinson's disease. In addition, anionic nanoplastics can induce vascular endothelial leakiness, thereby harboring a paracellular route for their systemic and cerebral access. Yet causality remains unproven in implicating nanoplastics for neurodegeneration in the absence of standardized human exposure data, mechanistic specificity, and epidemiological evidence, especially considering the supra-environmental doses employed. Here, we synthesize current knowledge, examine barriers to causal understanding, and propose a roadmap to advance this emerging scientific frontier of great public concern and inform future strategies for sustainable materials innovation.

A BioLiving Periosteum Evokes Centripetal Regeneration in Challenging Bone Defects

Fri, 08 May 2026 08:26:17 -0700

Large bone defects often suffer from insufficient central healing. This study engineers a BioLiving periosteum that mimics the native structure. It sequentially delivers remote chemical cues and contact physical cues in a signaling-relay manner, effectively recruiting and guiding endogenous cells toward the defect center. This strategy achieves centripetal bone regeneration, offering a promising therapeutic approach for severe bone defects.

ABSTRACT

Large bone defects often exhibit compromised bone healing in the central region. Natural periosteum serves as a bioactive barrier by preventing unwanted fibroblast infiltration and providing regenerative cells. However, a significant gap remains in obtaining desirable central bone healing in large bone defects, and the challenge of achieving a balance between the dense barrier structure and bioactive functionality remains unresolved. Herein, a BioLiving periosteum is engineered to recapitulate key features of native periosteum. The middle mini-tissue is obtained by the liquid substrate culture (LSC) method, and encapsulated between a fiber-guiding layer and a recruitment layer, both of which feature topological structures. The LSC method endows endothelial cells (ECs) with an elevated glycolytic activity, facilitating their transition to a type-H phenotype, which could secrete multiple growth factors (chemical signals) to recruit endogenous cells. Subsequently, the recruited cells are further guided by the radial topological structure (physical signals) to migrate toward the central area. The combination of remote chemical cues and contact physical cues functions in a signaling-relay manner, effectively promoting bone formation in the central area of the defect. Thus, the BioLiving periosteum triggers centripetal bone regeneration through a physicochemical signaling-relay mode, representing a promising therapeutic strategy for severe bone defects.

Farnesyltransferase Deficiency in Cardiomyocytes Initiates Senescence and Contributes to Cardiac Fibrosis

Fri, 08 May 2026 08:26:17 -0700

Lipid overload suppresses SREBF2-mediated FNTB expression, leading to defective Lamin A maturation and nuclear envelope instability. This nuclear catastrophe triggers a pro-fibrotic senescence program in cardiomyocytes. Notably, restoring nuclear integrity via AAV9-based gene therapy effectively attenuates cardiac remodeling, identifying the farnesylation-senescence axis as a promising therapeutic target for lipotoxic cardiomyopathy.

ABSTRACT

Cardiomyocyte senescence contributes to cardiac fibrosis, yet the molecular mechanisms remain unclear. Farnesylation is a post-translational modification critical for cholesterol metabolism and is mediated by the farnesyltransferase beta subunit (FNTB). However, its specific role in cardiomyocyte senescence and cardiac fibrosis remains unclear. Cardiomyocyte-specific Fntb knockout mice were generated to assess cardiac remodeling. RNA sequencing, DNA damage assays, and senescence markers identified molecular pathways. Mechanistic studies included nuclear envelope ultrastructure analysis, laminA assessments. Clinical relevance was assessed via human heart samples from hyperlipidemic patients. In cardiomyocyte-specific Fntb knockout mice, deletion of FNTB induced progressive cardiac fibrosis that preceded hypertrophy development. Pressure overload exacerbated dysfunction in knockouts, revealing fibrosis-dependent vulnerability. Mechanistically, loss of FNTB impaired laminA maturation, destabilized nuclear envelope integrity, and triggered DNA damage response activation, resulting in cardiomyocyte senescence. Senescent cardiomyocytes secreted elevated Tgf-β2 and Gdf15, driving cardiac fibroblast activation. Upstream regulation studies revealed that lipid overload suppressed Fntb transcription via Srebf2 downregulation, recapitulated in hyperlipidemic human hearts showing reduced FNTB expression. Notably, AAV9-mediated Fntb overexpression attenuated cardiac fibrosis in mice fed a high-fat diet. Collectively, our results demonstra that lipid overload suppresses FNTB expression in cardiomyocytes. This deficiency compromises nuclear integrity, triggering a senescence program and driving cardiac fibrosis. These findings uncover a novel mechanism of lipotoxic cardiomyopathy and suggest that farnesylation warrants further investigation as a potential target to fibrotic remodeling in metabolic heart diseases.

Sirt3 Genetically Engineered Apoptotic Bodies Alleviate Skeletal Aging by Limiting Aggravated NLRP3 Inflammasome Activation of Senescent Macrophages

Fri, 08 May 2026 08:26:17 -0700

The senescence of macrophages leads to a decrease in the expression of Sirtuin3 (Sirt3), which in turn aggravates the NLRP3 inflammasome activation and IL-1β secretion, thereby promoting the aging-related osteoporosis. Sirt3-enriched apoptotic bodies (ABs-Sirt3) generated through genetic editing approaches can alleviate skeletal aging by targeting macrophages for the delivery of Sirt3.

ABSTRACT

Skeletal aging is characterized by increased fragility, reduced bone mass, and deterioration of bone microstructure. Although aging-related immune dysfunction of macrophages, namely immunosenescence, is known to contribute to this process, the underlying mechanism remains poorly understood. Here, we find that the senescence of macrophages leads to a decrease in the expression of Sirtuin3 (Sirt3), which in turn leads to increased basal and lipopolysaccharides (LPS)-induced protein expression of NLRP3 and facilitates the assembly of NLRP3 inflammasome in macrophages that mediates aging-related osteoporosis. Given the phagocytic property of macrophages, we develop a genetically engineered apoptotic body-based platform for targeted delivery of Sirt3 to macrophages and verify that Sirt3-enriched apoptotic bodies (ABs-Sirt3) delay skeletal aging by promoting ubiquitination and degradation of NLRP3. Our work reveals that Sirt3 plays a key role in regulating aggravated inflammatory responses that accelerate skeletal aging during macrophage senescence and illustrates a novel nanotechnology-based therapeutic approach targeting immune senescence-induced acceleration of skeletal aging, which may provide potential therapeutic value for human patients with age-related osteoporosis.

Intracellular Aβ42 Sequestration by a Serine Protease Mitigates Neurotoxicity in a Drosophila Alzheimer's Disease Model

Jingyun Su, Meng Yang, Xinfeng Wang, Pa Wu, Zongzhao Zhai — Fri, 08 May 2026 08:26:17 -0700

Emerging evidence suggests that intraneuronal Aβ accumulation represents an early pathogenic event in Alzheimer's disease (AD). Using Drosophila AD model, this study shows that a nonsecreted serine protease Yip7 physically interacts with Aβ. This causes intraneuronal Aβ accumulation but surprisingly reduces the associated neurotoxicity, arguing that sequestrating intracellular amyloids can be a possible therapeutic strategy for AD.

ABSTRACT

Emerging evidence suggests that intraneuronal Aβ accumulation represents an early pathogenic event in Alzheimer's disease (AD), preceding extracellular plaque formation and neuroinflammatory responses. However, whether targeting intracellular Aβ can halt disease progression and how this can be achieved in vivo remain unknown. While investigating the brain transcriptional responses to Aβ pathology, we identify a neuroprotective role for the serine protease Yip7 in a Drosophila AD model. Neuronal overexpression of yip7 alleviates multiple Aβ42-induced deficits, including declines in locomotor activity, impaired proteostasis, increased brain aging and neuronal death, and shortened lifespan. Unlike canonical digestive proteases, Yip7 is not secreted but instead localized to the endosomal/lysosomal compartments via a putative transmembrane domain initially predicted as a signal peptide. Crucially, Yip7's neuroprotective function depends on its proper subcellular localization rather than the catalytic triad. Mechanistically, rather than eliminating Aβ, Yip7 binds intracellular Aβ42 to increase its neuronal retention, and this unexpectedly reduces Aβ42 toxicity to the organism. Finally, transcriptomics reveals that protection against Aβ42 toxicity by Yip7 is associated with selective suppression of Aβ-upregulated genes including those codingribosomal proteins and molecular chaperones for protein folding. Together, these findings introduce a novel concept that intracellular sequestration of Aβ can be explored to mitigate its neurotoxicity.

NIR‐II Imaging‐Guided Photothermal Activation of a TRPV4‐Targeted Nanoplatform Delivering Cycloastragenol to Promote Microglia Reprogramming and α‐Synuclein Clearance in Parkinson's Disease

Fri, 08 May 2026 08:26:17 -0700

ABSTRACT

Current therapies for Parkinson's disease (PD) fail to concurrently address α-synuclein (α-syn) aggregation and microglia-mediated neuroinflammation. Herein, we engineer a near-infrared-II (NIR-II) phototheranostic nanoplatform, CAG/FD1080@MM-aTRPV4, for synergistic regulation of microglial function and real-time monitoring of PD pathology. We first encapsulated cycloastragenol (CAG), a bioactive compound derived from Astragalus, into liposomes. These liposomes were then fused with biomimetic microglial membrane-loaded FD1080 photothermal imaging agent, followed by modification with a transient receptor potential vanilloid 4 (TRPV4)-targeting antibody. In vitro studies using α-syn-treated cultured microglia and in vivo studies in an α-syn-overexpressing mouse model collectively demonstrate the efficacy of our strategy. It not only enables precise microglial delivery of CAG to reprogram metabolism but also sustains lysosomal function via photothermal activation of the TRPV4/CaMKKβ/AMPK/mTOR pathway, ultimately enhancing phagocytosis. Importantly, the encapsulated FD1080 (for microglial tracking) and an anti-α-syn-conjugated indocyanine green (anti-α-syn-ICG) probe enable dual-modality NIR-II photoacoustic-fluorescence imaging, allowing real-time visualization of both microglial dynamics and α-syn clearance. This work pioneers a photothermal immunomodulation strategy using a Chinese herb-derived compound, presenting a versatile theranostic platform and novel mechanistic insights for microglia-targeted PD therapy.

Molecularly Engineered Phenoxazinone‐Skeleton Cascade‐Activated NIR Probes for Monitoring Fe2+/Viscosity in Ferroptosis‐Mediated Parkinson's Disease

Fri, 08 May 2026 08:26:17 -0700

A series of Fe² ⁺/viscosity cascade-activated NIR fluorescence probes (NP1–5) are synthesized, and NP3 is selected for its optimal properties. To verify application of NP3 in ferroptosis intervention in PD, PQR NPs, is constructed by NP3 and quercetin self-assembling. The result demonstrate that PQR NPs alleviate ferroptosis-induced dopaminergic neuron loss and could monitoring Fe² ⁺/viscosity fluctuation in ferroptosis of PD models.

ABSTRACT

Parkinson's disease (PD) is the second most common neurodegenerative disease, in which ferroptosis may be the crucial event leading to dopaminergic neuron death. Accumulated ferrous ions (Fe²⁺) and increased intracellular viscosity promote of ferroptosis. Precisely monitoring Fe²⁺/Viscosity, especially in ferroptosis, is crucial for PD theranostic. However, a feasible strategy is lacking. In this study, series of Fe²⁺/Viscosity cascade-activated near-infrared fluorescence probes (NP1–5) are synthesized. Through optical characterization and theoretical calculations, NP3 is selected as the optimal probe to monitor Fe² ⁺/Viscosity via redox reactions and twisted intramolecular charge transfer processes. To verify this concept in the context of ferroptosis intervention in PD, an innovative nanoplatform is constructed based on NP3 and quercetin, modified with rabies virus glycoprotein-29 and defined as PQR nanoparticles (PQR NPs). In vitro and in vivo experiments demonstrate that PQR NPs not only alleviate ferroptosis-induced loss of dopaminergic neurons by reducing oxidative stress and neuroinflammation, mitigating α-synuclein aggregation, and restoring mitochondrial function, but also could monitor the elevated Fe² ⁺/Viscosity in ferroptosis of PD models. Present study developed a facile tool for monitoring Fe²⁺/Viscosity in ferroptosis. The findings have strong application potential in theranostics of PD and other ferroptosis related diseases.

Inhibiting cGAS‐STING to Preserve Mitochondrial–Nuclear Communication and Stemness in Young Tendon Stem Cells: A Hydrogel Strategy against Age‐Related Tendinopathy

Fri, 08 May 2026 08:26:17 -0700

A dual-targeting strategy to rejuvenate aged tendons. A reactive oxygen species (ROS)-responsive hydrogel co-delivers a selenium nanozyme (scavenges ROS) and a STING inhibitor to tendon stem cells. This combined action restores mitochondria–nucleus communication, alleviates cellular senescence, and rejuvenates tendon regeneration, offering a novel therapy for age-related tendinopathy.

ABSTRACT

Age-related tendinopathy is common in the elderly. Their refractory nature is linked to low cellular density and poor blood supply of tendons. Key pathological features in aged tendons include the accumulation of senescent tendon-derived stem cells (TDSCs), a decrease in young TDSCs, and an imbalance in the inflammatory microenvironment caused by reactive oxygen species (ROS). Among these, impaired mitochondria–nucleus communication is a central mechanism in disease progression. This study develops a ROS-responsive dual-targeted hydrogel (P/H@Lipo) loaded with selenium nanocatalysts (HPSe) and the STING inhibitor H-151 in liposomes (L-Lipo@H-151). This system releases L-Lipo@H-151 in response to ROS within the inflammatory environment, targeting it to TDSCs to inhibit the cGAS-STING pathway. The simultaneously released HPSe effectively reduces mtDNA leakage and cGAMP production, thereby strengthening the blockade of the cGAS-STING pathway. This process maintains mitochondrial–nuclear communication, which in turn preserves the stemness of young TDSCs by preventing their senescence. Mechanistic studies indicate that HPSe boosts self-renewal and tendinogenic differentiation in young TDSCs by inhibiting the Hippo signaling pathway. In summary, this study develops a novel therapeutic paradigm that targets the mitochondrial–nuclear communication to combat age-related tendinopathy.

Postoperative Stress Accelerates Atherosclerosis Through Inflammatory Remodeling of the HDL Proteome and Impaired Reverse Cholesterol Transport

Fri, 08 May 2026 08:26:17 -0700

The study shows that noncardiac surgical inflammation rapidly disrupts HDL function and cholesterol efflux in mice and human patients. Impaired reverse cholesterol transport after surgery drives rapid lipid accumulation, NETosis, and apoptosis within atherosclerotic plaques. This acute remodeling heightens plaque vulnerability by 15 days post-surgery. Enhancing cholesterol transport with rh-APOA1 emerges as a promising strategy to counter surgery-induced plaque destabilization.

ABSTRACT

Over 10 million patients undergoing non-cardiac surgery each year face major cardiovascular complications within 30 days, many due to destabilized atherosclerotic plaques. Reverse cholesterol transport (RCT), driven by HDL and Apoa1, protects against plaque progression, but the effects of surgical inflammation on this pathway remain unclear. Using an abdominal laparotomy model in ApoE^−/− mice on a Western diet, we isolated the impact of surgical inflammation without confounding blood loss. Surgery acutely impaired RCT and cholesterol efflux, with inflammatory remodeling of HDL marked by elevated SAA1/2 and reduced Apoa1. Plaques exhibited higher intracellular lipids, PLIN2 expression, and cleaved caspase-3, indicating lipid-driven apoptosis. Both leukocytic and non-leukocytic foam cells showed increased PLIN2, with apoptosis concentrated in PLIN2^hi cells. Using a novel dual-label, dual-cell-type in vivo RCT model, we found that surgery significantly impaired macrophage RCT while VSMC RCT remained largely unaffected, highlighting foam cell subtype-specific vulnerability to surgical inflammation. These findings were mirrored in general surgery patients, whose postoperative plasma exhibited markedly reduced cholesterol efflux capacity. In mice, rh-APOA1 treatment partially restored RCT and reduced plaque lipid accumulation. Surgical inflammation rapidly disrupts HDL function and RCT, promoting foam cell apoptosis and plaque destabilization. Timely Apoa1 restoration may help reduce postoperative cardiovascular risk.

TEAD1 Enhances Exosome Secretion and Promotes Exosome‐Mediated Tissue Regeneration

Mon, 04 May 2026 01:40:50 -0700

TEAD1 functions as a crucial molecular switch regulating exosome secretion in various cell types. TEAD1 enhances exosome secretion by upregulating key proteins associated with exosome secretion, including RAB11, CD9, and SNAP23. This study reveals a novel role for TEAD1 in regulating exosome secretion and tissue regeneration, particularly in diabetic wound healing and spinal cord injury models.

ABSTRACT

Exosomes serve as intercellular communication vectors and are involved in a broad range of physiological functions. Although exosome-based therapies have demonstrated diverse functional potential, the regulatory mechanisms underlying their biogenesis and secretion remain poorly understood. Here, we report that TEAD1 functions as a molecular switch, dramatically enhancing the synthesis and secretion of exosomes. Mechanistically, TEAD1 enhances exosome secretion by promoting the expression of exosome secretion-associated proteins RAB11, CD9, and SNAP23. We found that TEAD1 enhances exosome secretion from adipose-derived mesenchymal stem cells, thereby promoting skin wound healing in diabetic mice. Similarly, TEAD1 promotes the release of exosomes from bone marrow-derived mesenchymal stem cells, thereby facilitating spinal cord injury (SCI) repair. Our study elucidates a novel role for TEAD1 in driving exosome secretion in different cell types, highlighting the therapeutic potential of TEAD1 in enhancing tissue regeneration, particularly in diabetic wound healing and SCI repair.

Atrophic Skeletal Muscle‐Derived Extracellular Vesicles Transfer miR‐125a‐5p to Inhibit Bone Formation in Osteoporosis during Aging

Mon, 04 May 2026 01:40:50 -0700

A muscle-bone endocrine pathway in aging is revealed in which extracellular vesicles released from atrophic skeletal muscle (Aged-SKM-EVs) inhibit bone formation. These EVs deliver miR-125a-5p to osteoblasts, thereby suppressing the SIRT7-Sp7 signaling axis and osteogenic differentiation. Therapeutic targeting of Aged-SKM-EVs or miR-125a-5p alleviates sarcopenia-associated bone loss.

ABSTRACT

Understanding how skeletal muscle influences bone formation is essential for uncovering the mechanisms of muscle-bone communication and developing therapies for osteoporosis. Here, we demonstrate that extracellular vesicles (EVs) derived from atrophic skeletal muscle (Aged-SKM-EVs) inhibit bone formation during aging. Utilizing a muscle-specific EV tracking transgenic mouse model, we found that Aged-SKM-EVs were significantly increased and taken up by osteoblasts in bone during aging. Notably, pharmacological blockade of muscle EV generation via a skeletal muscle-targeted delivery of GW4869 significantly restored osteoblast activity and alleviated bone loss in aged mice. Functional studies revealed that Aged-SKM-EVs suppressed bone formation and inhibited osteogenic differentiation both in vivo and in vitro. Mechanistically, we identified miR-125a-5p as a key cargo enriched in EVs from sarcopenic patients and aged mice. Muscle-specific overexpression of miR-125a-5p inhibited osteogenesis and exacerbated muscle atrophy and bone loss, whereas silencing miR-125a-5p in skeletal muscle effectively reversed these effects. Further investigation demonstrated that miR-125a-5p inhibits osteogenic differentiation by directly targeting Sirt7 in preosteoblasts, thereby disrupting SIRT7-mediated histone deacetylation at the Sp7 promoter and suppressing Sp7 transcription. Our findings reveal a novel endocrine pathway from muscle to bone mediated by EV-associated miRNA and highlight miR-125a-5p as a promising therapeutic target for sarcopenia-related osteoporosis.

The Age‐Dependent Resident Myonuclear Multi‐Omic Response to an Acute Skeletal Muscle Hypertrophic Stimulus in Mice

Mon, 04 May 2026 01:40:50 -0700

Resident myonuclei are the molecular “control centers” for large multinuclear muscle fibers. It is presumed that, with aging, these control centers become compromised and contribute to delayed or blunted muscle adaptive potential. This study is a detailed roadmap that exposes how young versus aged myonuclei respond to a hypertrophic loading stimulus across several molecular layers and at single myonucleus resolution.

ABSTRACT

A detailed analysis of how muscle fiber nuclei (myonuclei) respond to a hypertrophic stimulus could provide a critical step toward understanding compromised skeletal muscle plasticity with age. We used recombination-independent doxycycline-inducible myonucleus-specific fluorescent labelling, tissue RNA-sequencing, myonuclear DNA methylation analysis, multi-omic integration, and single myonucleus RNA-sequencing (smnRNA-seq) to define the molecular characteristics of adult (6–8 month) and aged (24 month) murine skeletal muscle after acute mechanical overload (MOV). In adult and aged MOV muscles, we found that: 1) similarities in the transcriptional response to loading—specifically in metabolism genes – were partly explained by a post-transcriptional microRNA-mediated mechanism that we corroborated using an inducible muscle fiber-specific miR-1 knockout model, 2) differences in age-dependent transcriptional responses were linked to the magnitude and location of differential DNA methylation in resident myonuclei, specifically around genes such as Myc, Runx1, Mybph, Ankrd1, collagen (Col) genes, and minichromosome maintenance (Mcm) genes, 3) adult and aged resident myonuclear transcriptomes had differing enrichment for innervation-related transcripts as well as unique transcriptional profiles in an Atf3+ “sarcomere assembly” population after MOV, and 4) cellular deconvolution analysis and smnRNA-seq supports a role for neuromuscular junction regulation in age-specific hypertrophic adaptation. These data are a roadmap for uncovering molecular targets to enhance aged muscle adaptability.

Nanoparticle‐Mediated Immunometabolic‐Epigenetic Remodeling Enhances Schwann Cell‐Macrophage Interaction for Sciatic Nerve Regeneration

Mon, 04 May 2026 01:40:50 -0700

A biomimetic Prussian White nanoparticle (PW) is engineered to achieve long-term local retention and orchestrate immunometabolic-epigenetic remodeling for sciatic nerve regeneration. PW directly targets hexokinase 2 to suppress glycolysis, thereby elevating α-ketoglutarate and driving Kdm4a/b-mediated demethylation of H3K9me3. This epigenetic activation polarizes macrophages toward a pro-regenerative S100a4⁺ phenotype that secretes itaconate, which in turn enhances Schwann cell proliferation under inflammatory stress, leading to robust functional recovery.

ABSTRACT

Peripheral nerve regeneration continues to pose a significant clinical challenge, primarily attributable to the inherently limited regenerative capacity of axons and the intricate inflammatory microenvironment that develops following injury. While immunometabolic modulation has emerged as a promising therapeutic avenue, achieving precise and sustained intervention within the injury microenvironment remains technically challenging. Here, we introduce a biomimetic Prussian White nanoparticle (PW) that facilitates long-term local retention and drives coordinated immunometabolic-epigenetic remodeling to promote sciatic nerve regeneration. Through integrated multi-omics analyses, we identify a previously unrecognized S100a4⁺ macrophage substate, which is epigenetically activated via PW-induced accumulation of α-ketoglutarate and subsequent Kdm4a/b-mediated demethylation of the repressive histone mark H3K9me3 at the S100a4 gene locus. Furthermore, these reprogrammed macrophages secrete itaconate, a previously unidentified neuro-immune mediator, which effectively supports Schwann cell proliferation under inflammatory stress. This nanoparticle-enabled metabolic-epigenetic dialogue between macrophages and Schwann cells markedly enhances functional and structural recovery in both rodent and canine models of sciatic nerve injury. Our findings establish a paradigm of material-mediated cell reprogramming via coordinated immunometabolic-epigenetic remodeling, offering a versatile and translatable strategy with broad potential for treating neurodegenerative disorders.