Natural killer (NK) cells are innate cytotoxic lymphocytes capable of eliminating malignant cells independent of prior antigen sensitization, thereby constituting a critical first-line defense in tumor immunosurveillance. Within the tumor microenvironment (TME), metabolic dysregulation profoundly impairs NK cell effector function, and accumulating studies have investigated the regulatory effects of extracellular metabolites on NK cells. This review systematically delineates the direct mechanistic interplay between extracellular metabolites and NK cell antitumor immunity, with particular emphasis on their roles as structural components, bioenergetic substrates, metabolic reprogramming inducers, modification donors, gene transcription regulators, stress response mediators, intracellular pH modulators, and ligands engaging cognate receptors to initiate downstream signaling cascades. Furthermore, we discuss the therapeutic strategies targeting metabolites to potentiate NK cell functionality, encompassing modulation of metabolite availability within the TME and exploitation of metabolite-sensitive signaling axes. In addition, combination of metabolic interventions with other modalities, such as adoptive NK cell transfer and anti-programmed cell death protein 1/programmed death-ligand 1 therapy, is also evaluated for prospective applications. This review provides a conceptual framework for understanding the metabolic regulation of NK cells, highlighting emerging directions for advancing NK-cell-centered cancer immunotherapy through metabolic modulation.

Antioxidant nanozymes regulate reactive oxygen species homeostasis by mimicking the core catalytic functions of natural antioxidant enzymes, including superoxide dismutase-, catalase-, and glutathione peroxidase-like activities. The clinical translation of natural antioxidant enzymes has long been hampered by inherent limitations: short in vivo half-life, susceptibility to inactivation under physiological conditions, cumbersome purification processes, high production costs, non-negligible immunogenicity, and limited targeting capacity. In contrast, antioxidant nanozymes can overcome these bottlenecks with superior structural stability, tunable catalytic activity, low preparation cost, and flexible multifunctional modification. Guided by the catalytic mechanisms of natural enzymes, researchers have established rational design strategies for antioxidant nanozymes. To date, a diverse array of antioxidant nanozymes have been developed, with promising applications in multiple biomedical fields, including inflammatory diseases, ischemia–reperfusion injury, neurodegenerative disorders, and cancer adjuvant therapy. Notably, landmark clinical progress has been achieved: The catalytic nanocrystal suspension CNM-Au8, a therapeutic candidate for amyotrophic lateral sclerosis, has advanced to phase II clinical trials. This review systematically summarizes the core catalytic mechanisms of antioxidant nanozymes, clarifies the structure–activity relationships between rational material design and catalytic performance, reviews the latest advances in their biomedical applications, and dissects the key bottlenecks restricting preclinical research and clinical translation. It aims to provide rational design principles for researchers in this field, reduce empirical trial and error in material development, and provide guidance for the further optimization and clinical translation of antioxidant nanozymes.

Communications between organs contribute to propel physiological functions, as well as pathological processes. Growing evidence indicates that bone is continuously regulated by multiple layers of endocrine, immune, metabolic, and neural networks. The common bone diseases, including osteoporosis, osteoarthritis, rheumatoid arthritis, and intervertebral disc degeneration, are reported with tight associations to other nonbone organs. These organ–bone axes emphasize the interorgan communications that maintain the bone homeostasis and maintain individual health. In this review, we systematically summarize recent advances in the organ–bone communications, highlighting mechanistic innovations, such as the gut–bone–immune axis, neuro–immune–bone integration, hypothalamic–pituitary–adrenal axis, adipo–neuro–bone axis, and their connections with bone pathophysiology. Furthermore, we highlight circulating biomarkers and imaging advances reflecting organ–bone crosstalk. Finally, we discuss the clinical relevance, current research gaps, and unsolved questions of organ–bone communications in the diagnostic stratification, treatment selection, and multidisciplinary management of bone diseases.

The intractability of diabetic bone defects mainly results from derailed inflammation. While peripheral neuropathy is a common comorbidity, whether sensory dysfunction contributes to uncontrolled inflammation in diabetes is poorly understood. Here, within diabetic bone defects, we show that diminished sensory innervation is coupled with disrupted immune dynamics, characterized by both delayed neutrophil chemotaxis and abnormal neutrophil retention that resulted from impaired macrophage efferocytosis. Therefore, we design a chocolate chip cookie-like scaffold, in which the surface-embedded microspheres function as “chips” enabling burst interleukin-8 (IL-8) release, while the surrounding matrix provides sustained nerve growth factor release from silk fibroin matrix. Timely neutrophil chemotaxis induced by IL-8 triggers bone healing via stem cell recruitment, which is reinforced by sensory innervation by inducing neutrophil N2 polarization. Notably, macrophages preferentially established intimate physical proximity to outgrowing neurites to form a synapse-like structure, where they restore efferocytosis driven by neuronal Galectin-3. Moreover, spatiotemporally regulating neuroimmune circuit enhances mandibular bone regeneration in diabetic rats, highlighting the therapeutic potential of neuroimmune interaction in programming diabetic inflammation resolution.

Background: Asthma involves chronic inflammation linked to metabolic reprogramming, but how metabolites reshape epigenetics through posttranslational modifications remains unclear. Methods: We used house dust mite (HDM)-induced asthmatic mice with multiomics analyses (metabolomics, posttranslational modification-proteomics, and chromatin immunoprecipitation sequencing) and validated findings through gene editing and adeno-associated virus interventions. Results: Asthmatic airways showed lactate-driven glutaminolysis, causing lactate/succinate accumulation. Phosphoenolpyruvate carboxykinase 2 (PCK2) succinylation at K100 enhanced stability by antagonizing ubiquitination, creating a lactate-generating feedback loop. Accumulated lactate triggered polyglutamine-binding protein 1 (PQBP1) lactylation at K223, enabling protein arginine methyltransferase 5 (PRMT5)/WD repeat domain 77 complex inhibition. This erased H4R3me2s repressive marks from proinflammatory gene promoters, particularly mitogen-activated protein kinase pathway genes, causing transcriptional derepression. Airway epithelium-specific Pqbp1 knockout reduced inflammation, goblet cell hyperplasia, and T helper 2 responses. Pck2-short hairpin RNA or oxamate treatment ameliorated asthmatic pathology. Conclusion: We identified a PCK2–lactate–PQBP1–PRMT5 axis linking metabolic reprogramming to epigenetic dysregulation in asthma. PCK2-K100 succinylation drives lactate accumulation, inducing PQBP1-K223 lactylation that inhibits PRMT5 and activates inflammatory genes, representing a therapeutic target for asthma.

Vehicle–road wear microplastics (VRWMPs) are microplastic-sized polymer-containing particles generated from the vehicle–road system, including tire–road wear particles (TRWPs) as the dominant composite class and other polymer-bearing wear debris (e.g., road marking wear). Their complex chemical composition and wide particle size distribution pose potential ecological risks. However, their impacts on ecosystems have long been overlooked because overlapping terminology (e.g., TRWP versus broader non-exhaust emissions) and nonstandardized characterization methods hinder cross-study comparability, while a tire-centered research focus and limited field monitoring obscure the contribution of pavement materials and realistic exposure scenarios. Existing studies largely emphasize tire-derived contributions, while the role of pavement materials remains underrepresented, resulting in an incomplete understanding of VRWMP formation mechanisms. In addition, limited long-term and systematic monitoring data constrain current knowledge of VRWMP migration, transformation, and environmental risks. From a road engineering perspective, this review synthesizes the full lifecycle of VRWMP, from generation to environmental fate. It focuses on formation mechanisms, preparation and characterization methods, migration, and transformation processes within roadway systems, and associated ecological and human health effects. Evidence indicates that VRWMP generation is jointly controlled by tire characteristics and pavement materials, yet a standardized characterization framework is still lacking. The migration and transformation of VRWMP are difficult to model due to data scarcity and pronounced regional variability related to geography, climate, and traffic conditions. Soil and aquatic environments represent major sinks, and exposure pathways such as inhalation may induce adverse biological effects, including oxidative stress and DNA damage. With the increasing complexity of pavement materials, establishing full-chain control of VRWMP, from generation to environmental fate, is becoming an urgent research priority. This review provides a scientific basis for advancing cleaner and more sustainable transportation infrastructure.

Real-time moisture sensing is crucial for environmental monitoring and food safety. However, conventional humidity sensors relying on moisture-induced changes in conductivity or capacitance are often constrained by sluggish water adsorption–desorption kinetics and inefficient ion transport through disordered nanochannels. Here, we develop cellulose aerogel fibers derived from natural rattan, featuring hierarchical and interconnected porosity, to enable ultrafast hydrovoltaic moisture sensing. The tailored pore network expedites the diffusion of trace moisture and substantially amplifies the solid–liquid interfacial area within the fiber, thereby boosting the formation of electric double layers and enhancing water-ion coupling. Consequently, the self-powered sensor delivers a detectable voltage response within 70 ms upon exposure to only 10 μl of water microdroplets, achieving both rapid detection and high sensitivity. Moreover, the device exhibits versatile responsiveness to multiple environmental parameters, and its sensing behavior can be readily tuned by manipulating the fiber configuration (linear, helical, and branched). All 3 configurations achieve a fast response to approximately 0.1 V within 70 to 310 ms, followed by a voltage increase to 0.49 to 0.63 V within 3 to 5 s. This work highlights the critical role of porosity engineering in cellulose aerogel fibers and provides a new strategy for developing high-performance biomass-based hydrovoltaic sensing systems.

The clinical utility of nanobodies in solid tumor therapy is constrained by a fundamental biophysical trade-off: rapid renal clearance necessitates half-life extension, which in turn demands ultrahigh affinity to prevent dissociation from the target under systemic washout conditions. While generative artificial intelligence has substantially advanced structure prediction, it often fails to resolve the subtle energetic frustrations at protein–protein interfaces required for affinity maturation. Here, we present a physics-informed artificial intelligence framework that integrates AlphaFold 3 structural priors with molecular dynamics simulations to rationally design a picomolar anti-carcinoembryonic antigen nanobody. By employing variable dielectric molecular mechanics/generalized Born surface area decomposition, we identified interfacial residues that were structurally permissible but thermodynamically suboptimal. We subsequently constructed a focused library to resolve these bottlenecks through electrostatic optimization, desolvation penalty minimization, and van der Waals packing refinement. This strategy achieved a 99% binding positivity rate and yielded variants with picomolar affinity (K_D ≈ 44 pM)—an ~306-fold improvement over the parental clone—without compromising thermal stability (T_m > 63 °C). To translate these biophysical gains into therapeutic efficacy, we engineered bispecific nanobodies fusing the affinity-matured domains with an anti-human serum albumin binder. In vivo longitudinal imaging of colorectal cancer xenografts revealed a “lock-and-hold” phenotype, characterized by deep intratumoral penetration and sustained retention (>168 h). This work demonstrates that coupling geometric deep learning with rigorous physical principles overcomes the inefficiencies of stochastic screening, providing a valuable framework that may be adapted for the rational development of high-potency biologics across various therapeutic targets.

The aging of the global population exacerbates the burden of age-related diseases; however, therapies that can intervene in fundamental aging processes are lacking. Senescent cells drive chronic inflammation and multitissue dysfunction through the secretion of proinflammatory and profibrotic senescence-associated secretory phenotype cells, making them emerging therapeutic targets. Although first-generation senolytic drugs have entered clinical trials, they face limitations such as insufficient targeting specificity and transient efficacy. The success of chimeric antigen receptor T cell (CAR T cell) therapy in cancer immunotherapy has validated its precision clearance capabilities as a “living drug”. This review systematically elaborates on the paradigm shift of extending CAR T cell therapy to aging medicine, from the discovery and validation of surface targets on senescent cells to a CAR engineering design tailored to the senescent microenvironment and from evidence of reversing fibrosis and improving metabolic function in preclinical models to the challenges of specificity, safety, and manufacturing faced in clinical translation. Finally, future directions for integrating technologies such as mRNA delivery and artificial intelligence are envisioned in this article, which proposes that CAR T cell therapy may drive the evolution of medicine from “treating single diseases” to “intervening in shared aging processes”, offering transformative strategies to achieve healthy aging.