Tissue infections such as osteomyelitis and infected skin wounds require therapies that can both eradicate drugresistant bacteria and promote tissue regeneration. Antimicrobial peptide therapy is an emerging anti-infective strategy, but it still faces two major challenges: achieving more rapid and potent antibacterial activity, and endowing peptides with dual functions of killing bacteria and promoting tissue repair. Here, we design a piezoelectric hexapeptide of Phe-Phe-Citrulline-Glu-Ser-Val (FFCitESV), which has ultrasound-activatable antimicrobial and promoting tissue healing activities. FFCitESV exhibits robust piezoelectricity and generates abundant singlet oxygen under low-intensity ultrasound, enabling rapid killing of MRSA in vitro. The peptide significantly enhanced hBMSCs osteogenic differentiation, ultrasound further amplified this effect via piezoelectric stimulation. In a rat tibial osteomyelitis model and a mouse infected skin-wound model, FFCitESV combined with ultrasound effectively controlled MRSA infection, reduced local and systemic inflammation, and markedly accelerated bone and skin defect repair compared with standard treatments. Multi-omics and histological analyses further clarified mechanisms. Transcriptomic analysis showed that FFCitESV plus ultrasound activated PI3K-Akt, Wnt, and calcium-related pathways associated with osteogenic differentiation and bone regeneration. In infected skin wounds, RNA sequencing revealed enhanced keratinocyte differentiation and activation of PI3K-Akt and JAK-STAT pathways, which together facilitated re-epithelialization and dermal repair. Overall, FFCitESV represents a biodegradable piezoelectric hexapeptide that enables on-demand disinfection and tissue regeneration, thereby serving as a versatile therapeutic platform for refractory osteomyelitis, infected skin wounds, and other infection-associated tissue defects.

Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication. However, the mechanisms governing their degradation remain poorly understood. In this study, we demonstrated that EVs are predominantly degraded via the lysosomal pathway. Mechanistically, MAP1LC3B recognizes SNX18 on the surface of endosome-escaped EVs to facilitate their sorting into the autolysosomal pathway for degradation. Leveraging this mechanism, we optimized the lysosomal sorting efficiency of EVs by surface display of LIR motifs and constructed an EV-based targeted protein degradation nanoplatform. The EV-based nanoplatform is highly modular and can be combined with monoclonal antibodies in a plug-and-play manner. It demonstrated remarkable efficiency and selectivity in degrading EGFR, PD-L1, and VEGF. Moreover, the nanoplatform demonstrated multi-targeting capability by simultaneously degrading EGFR and VEGF. Our findings uncover a previously unrecognized mechanism of EVs degradation and provide a novel strategy to harness the EVs degradation machinery as a nature-inspired nanoplatform for the degradation of multiple targeted proteins.

Macrophages eliminate apoptotic cells produced daily in the body through efferocytosis. Restricted clearance can cause inflammation-related diseases. In intervertebral discs (IVDs), apoptotic nucleus pulposus cells (NPCs) are difficult to effectively remove, and their accumulation can cause changes in the inflammatory microenvironment, disrupt IVD homeostasis, and lead to IVD degeneration (IDD). Here, we present chimeric antigen receptor-M-like engineered macrophages (CAR-eMs) with enhanced efferocytosis capacity for IDD treatment. Macrophages undergo phenotypic transformation and a reduction in phagocytic ability after phagocyting apoptotic NPCs, but their efferocytosis capacity recovers with upregulated brain-specific angiogenesis inhibitor 1 (BAI1) expression. We develop a CAR-eM system with enhanced BAI1 expression and an IVD circular microneedle (MN) delivery system that utilizes arrays of MNs to deliver CAR-eMs into the deep IVD layers, thereby clearing apoptotic NPCs, ameliorating the inflammatory microenvironment, and repairing damaged IVDs. Our study explores the therapeutic potential of CAR-eM efferocytosis for IDD treatment.

Infected wounds present a high clinical incidence, and current treatments are inadequate in both effectively eliminating bacterial biofilms and continuously promoting tissue regeneration. To address these challenges, we develop a microwave-responsive thermoelectric nanocomposite of zinc oxide-bismuth telluride (ZnO-Bi2Te3) via hydrothermal synthesis for the treatment of biofilm infected wounds. The heterointerface within the nanocomposite enhances phonon scattering, while the ZnO component provides additional charge carrier transport pathways, collectively significantly improving the thermoelectric conversion performance. Under microwave irradiation, the ZnO-Bi2Te3 rapidly generates substantial amounts of reactive oxygen species (ROS), enabling efficient penetration and eradication of biofilms with an antibacterial rate of 99.2

Myelin deterioration impairs neural communication and may contribute to neurodegenerative diseases such as Alzheimer’s disease (AD). However, the spatiotemporal relationship between myelin degeneration and AD pathology remains unclear. We developed a novel imaging method—double-scan Cyto- and myelo-architecture (dsCMA)—that integrates multi-fluorescent labeling of cytoarchitecture and pathological markers with brightfield myelin staining on the same tissue sections. Coupled with computational tools for automated detection and quantification of amyloid-beta (Aβ) plaques and myelinated axons, dsCMA enables systematic analysis of Aβ–myelin interactions in 5xFAD mice and postmortem human AD tissues. In mice, we identified progressive, region-specific myelin disruption associated with Aβ accumulation, particularly in the hippocampus and cortex. Human samples revealed variable Aβ–myelin spatial relationships across individuals and regions, with evidence supporting a potential myelin origin for some plaques. These findings offer new insights into Aβ–myelin interplay and establish dsCMA as a scalable platform for histopathological analysis in translational and longitudinal AD research.

ABSTRACT Low back pain is a global health problem. Discogenic low back pain, the most common type of low back pain, is closely related to cartilage endplate (CEP) degeneration and inflammation. In this study, by constructing a rat model of lumbar spine instability (LSI) and combining biomechanical analysis with molecular biology techniques, we revealed the central role of the mechanosensitive channel Piezo2 in the vicious cycle of discogenic low back pain. The results revealed that abnormal mechanical stress triggers calcium influx and promotes CGRP release by activating Piezo2 in the dorsal root ganglion (DRG). CGRP synergizes with mechanical force to activate the IKKβ/NF‐κB pathway in CEP cells via the receptor RAMP1, which induces the secretion of IL‐6 and IL‐1β, and further sensitizes DRG neurons, forming a positive feedback loop. Macrophage depletion did not alleviate pain/inflammation. Targeted inhibition of Piezo2 (with AAV‐shPiezo2 gene silencing or omega‐3 fatty acids) or blockade of CGRP signaling (with Rimegepant) significantly alleviated pain‐related behaviors, suppressed inflammation, and delayed CEP degeneration. This study elucidated a novel mechanism by which mechanical‒neuroinflammatory interactions drive the progression of discogenic low back pain and provided a theoretical basis for the development of multitargeted combination treatment strategies.

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, yet there remains no effective therapeutic approach to reverse its progression, imposing a substantial socioeconomic burden. While multiple factors contribute to IVDD pathogenesis, cellular senescence has emerged as a critical risk factor associated with both the incidence and progression of IVDD. Aging and other damage factors drive nucleus pulposus cells (NPCs) toward a senescent phenotype characterized by increased secretion of proinflammatory factors, resulting in NPC dysfunction and tissue degeneration, which are hallmarks of IVDD. In this study, we demonstrated that PRMT2 deficiency disrupted arginine methylation-ubiquitination crosstalk, driving NPC inflammatory senescence and accelerating IVDD progression. Mechanistically, PRMT2 loss reduced FBXO7 methylation at Arg504, promoting the FBXO7-MED12 interaction to facilitate MED12 ubiquitination and subsequent proteasomal degradation. MED12 deficiency induced pathological R-loop accumulation, which activated the cytosolic DNA-sensing cGAS/STING axis, triggering inflammatory response cascades. Notably, engineered extracellular vesicles delivering MED12-overexpressing plasmids significantly inhibited NPC senescence and attenuated IVDD progression. Together, our findings establish that dysregulated methylation-ubiquitination crosstalk critically drives IVDD progression and reveal MED12 as a promising therapeutic target for ameliorating the impact of IVDD.

BACKGROUND:Osteoblast senescence is a central driverof age-related osteoporosis. Accumulating evidence shows that counteractingthis senescence can substantially mitigate bone loss. In this review, we summarize the hallmarks of osteoblast senescence, the signaling pathways involved, and therapeutic strategies that target osteoblast senescence tocombat age-related osteoporosis. METHODS:Chronic diseases associated with ageingpose a significant threat to human health. Studies have shown that osteoporosisis closely linked to the ageing process of the body and the senescence ofosteoblasts within the bone microenvironment. Counteracting the senescence ofosteoblasts and maintaining the balance of differentiation, proliferation andfunction between osteoclasts and osteoblasts has been a key focus in the research of age-related osteoporosis and bone loss. The biological behaviour andfunctionality of the osteoblast lineage related to senescence are modulated bya variety of targets, including signalling pathways, proteins and genes associated with ageing. This review aims to discuss the senescence-related characteristics of the osteoblast lineage, dissect the interplay and mechanisms between it and ageing-associated signalling pathways, proteinsand genes, as well as current strategies for the prevention and treatment ofosteoblast senescence. CONCLUSION:This review systematically examines the regulatory interactions among markers, therapeutic targets, and signalingpathways associated with osteoblast senescence, alongside current potential strategies for targeting this process. It provides more comprehensive information for future research into the complex mechanisms underlying age-related osteoporosis driven by osteoblast senescence. KEY POINTS:Osteoblast senescence is a key driver of age-related osteoporosis, disrupting bone formation and homeostasis. Aging impacts osteoblasts through multiple pathways, including telomere shortening, genomic instability, SASP secretion, and others. Bone loss related to osteoblast senescence involves the activation and crosstalk of multiple signaling pathways. The options for combating and treating osteoblast senescence toachieve anti-osteoporosis are numerous, but still challenging.

The medial prefrontal cortex (MPF) regulates emotions, stress responses, and goal-directed behaviors like attention and decision-making. However, the precise mechanisms underlying MPF function remain poorly understood, largely due to an incomplete characterization of its neural circuitry. Leveraging neuroanatomical, neurophysiological, and behavioral techniques, we present a detailed wiring diagram of the MPF, with a particular focus on the dorsal peduncular area (DP), an underexplored MPF area implicated in psychological stress, fear conditioning, anxiety, depression, and opioid addiction. Our analysis identifies the deep (DPd) and superficial (DPs) layers of the DP, together with the infralimbic area (ILA), as key components of the primary visceromotor cortex, that generate monosynaptic projections to regulate neuroendocrine, sympathetic, and parasympathetic functions in distinct, yet coordinated ways. Further, we demonstrate that the DP serves as a unique network hub for unidirectional cortical information flow, that integrates diverse cortical inputs and modulates social behavior. Based on the mesoscale connectome of entire MPF, we propose a unified MPF network model that regulates different aspects of motor actions associated with goal-directed behavior. This study provides novel insights into the complex role of the MPF in orchestrating physiological and behavioral responses to environmental stimuli in mammals.

Cellular mechanotransduction, essential for many biological functions, involves the conversion of mechanical signals into biochemical signals related to cell activities and metabolism. Physical factors in the local cellular microenvironment include external mechanical forces, mechanical stimulation generated by the extracellular matrix and intercellular mechanical interactions mediated through cell–cell adhesions. Intervertebral disc degeneration (IDD) is a complex pathological process involving diverse etiological contributors, such as mechanical wear, oxidative damage and nutritional deficiency. Notably, aberrant mechanical loading has been identified as a pivotal driver in both the initiation and progression of IDD. The mechanical microenvironment in intervertebral discs mainly includes pressure, tension, hydrostatic pressure, osmotic pressure and extracellular matrix stiffness. A thorough understanding of the mechanotransduction process of intervertebral disc cells in response to various mechanical stimuli and its regulatory mechanism is of great significance for the prevention and treatment of IDD. Here, therefore, we systematically review the research progress in understanding the mechanical microenvironment and mechanotransduction in IDD. Low back pain is a growing global health issue, especially as the population ages. It often results from intervertebral disc degeneration (IDD), which affects the discs that cushion the spine. These discs are primarily made of a jelly-like substance called nucleus pulposus, which helps to absorb stress on the spine. Researchers explored how mechanical forces affect IDD. They reviewed studies on how different types of mechanical stress impact nucleus pulposus cells. These forces can change cell behavior and lead to disc degeneration. The study focused on mechanotransduction, which is how cells convert mechanical signals into biochemical ones. This process involves structures such as integrins and ion channels that sense mechanical changes. The researchers found that abnormal mechanical stress can lead to cell damage and disc degeneration. Understanding these processes may aid in the development of therapies to slow or reverse IDD. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

The medial prefrontal cortex (MPF) regulates autonomic and neuroendocrine responses to stress1,2 and coordinates goal-directed behaviours such as attention, decision-making and social interactions3-8. However, the underlying mechanisms remain unclear due to incomplete circuit-level MPF characterization7. Here, using integrated neuroanatomical, physiological and behavioural approaches, we construct a comprehensive wiring diagram of the MPF, focused on the dorsal peduncular area (DP)-a poorly understood prefrontal area. We identify its deep (DPd) and superficial (DPs) layers, along with the infralimbic area, as major components of the visceromotor cortex that directly project to hypothalamic and brainstem structures to govern neuroendocrine, sympathetic and parasympathetic output. Notably, the DP functions as a network hub integrating diverse cortical inputs and modulating goal-directed behaviour through a largely unidirectional cortical information flow. On the basis of the mesoscale MPF connectome, we propose a unified network model in which distinct MPF areas orchestrate physiological and behavioural responses to internal and external stimuli.

Mitochondrial double-stranded RNA (mtdsRNA), a long-stranded RNA molecule generated by bidirectional transcription of the circular mitochondrial genome, can trigger the type 1 interferon response by activating pattern recognition receptors in the cytoplasm during mitochondrial dysfunction. However, its regulatory and pathogenic mechanisms in intervertebral disc degeneration are poorly understood. Here, we showed that mtdsRNA was abnormally elevated in degenerative nucleus pulposus tissues. Furthermore, we found that mtdsRNA leakage into the cytoplasm could cause MAVS oligomerization by binding to RLRs, and oligomerized MAVS could then promote nucleus pulposus cell pyroptosis by activating NLRP3. To further elucidate the upstream regulatory mechanism of mtdsRNA, we performed untargeted metabolomics analysis, which revealed that the downregulation of taurine under external stimuli could drive an imbalance in mtdsRNA homeostasis. RNA-seq further revealed that exogenous supplementation with taurine protected cells from mtdsRNA-induced pyroptosis by increasing mitophagy. In conclusion, our study links taurine metabolism, mitochondrial nucleic acids and pyroptosis and suggests that mtdsRNA is an important causative molecule and a potential therapeutic target in intervertebral disc degeneration.

Currently, classification of neuron types in the mouse thalamus remains largely incomplete. The anterior thalamic nuclei (ATN), a Papez circuit component, encompass the anterodorsal (AD), anteroventral (AV), and anteromedial (AM) thalamic nuclei. Structurally, the ATN facilitate communication among the neocortex, hippocampus, amygdala, and hypothalamus. Functionally, they play pivotal roles in learning, memory, spatial navigation, and goal-directed behaviors. Therefore, the ATN provide a promising avenue to investigate the relationship between structural and functional complexity with neuron type diversity. In male mice, comprehensive, systematically collected, pathway tracing data revealed several connectionally unique ATN cell populations, suggesting multiple parallel subnetworks run through each nucleus. Further, we applied genetic sparse labeling, brain clearing, 3D microscopic imaging, and computational informatics to morphologically characterize and catalog ATN neuron types. This study provides insights into how the prefrontal cortex, hippocampus, and amygdala interact through neuron type-specific ATN subnetworks to coordinate cognitive and emotional aspects of goal-directed behavior.

Study Design.We constructed finite element (FE) models of the cervical spine consisting of C2-C7 and predicted the biomechanical effects of different surgical procedures and instruments on adjacent segments, internal fixation systems, and the overall cervical spine through FE analysis.Objective.To compare the biomechanical effects between the zero-profile device and cage-plate device in skip-level multistage anterior cervical discectomy and fusion (ACDF).Summary of Background Data.ACDF is often considered the standard treatment for degenerative cervical spondylosis. However, the selection of surgical methods and instruments in cases of skip-level cervical degenerative disk disease is still controversial.Materials and Methods.Three FE models were constructed, which used noncontiguous 2-level Zero-P (NCZP) devices for C3/4 and C5/6, a noncontiguous 2-level cage-plate (NCCP) for C3/4 and C5/6, and a contiguous 3-level cage-plate (CCP) for C3/6. Simulate daily activities in ABAQUS. The range of motion (ROM), von Mises stress distribution of the endplate and internal fixation system, and intervertebral disk pressure (IDP) of each model were recorded and compared.Results.Similar to the stress of the cortical bone, the maximum stress of the Zero-P device was higher than that of the CP device for most activities. The ROM increments of the superior, inferior, and intermediate segments of the NCZP model were lower than those of the NCCP and CCP models in many actions. In terms of the IDP, the increment value of stress for the NCZP model was the smallest, whereas those of the NCCP and CCP models were larger. Similarly, the increment value of stress on the endplate also shows the minimum in the NCZP model.Conclusions.Noncontiguous ACDF with zero profile can reduce the stress on adjacent intervertebral disks and endplates, resulting in a reduced risk of adjacent segment disease development. However, the high cortical bone stress caused by the Zero-P device may influence the risk of fractures.

Objective To study the biomechanical characteristics of each tissue structure when using different 3D printing Cage in osteoporotic patients undergoing interbody fusion. Methods A finite element model of the lumbar spine was reconstructed and validated with regarding a range of motion and intervertebral disc pressure from previous in vitro studies. Cage and pedicle screws were implanted and part of the lamina, spinous process, and facet joints were removed in the L4/5 segment of the validated mode to simulate interbody fusion. A 280 N follower load and 7.5 N·m moment were applied to different postoperative models and intact osteoporotic model to simulate lumbar motion. The biomechanical characteristics of different models were evaluated by calculating and analyzing the range of motion of the fixed and cephalic adjacent segment, the stress of the screw-rod system, the stress at the interface between cage and L5 endplate, and intervertebral disc pressure of the adjacent segment. Results After rigid fixation, the range of motion of the fixed segment of model A-C decreased significantly, which was much smaller than that of the osteoporotic model. And with the increase of the axial area of the interbody fusion cages, the fixed segment of model A-C tended to be more stable. The range of motion and intradiscal pressure of the spinal models with different interbody fusion cages were higher than those of the complete osteoporosis model, but there was no significant difference between the postoperative models. On the other hand, the L5 upper endplate stress and screw-rod system stress of model A-C show a decreasing trend in different directions of motion. The stress of the endplate is the highest during flexion, which can reach 40.5 MPa (model A). The difference in endplate stress between models A-C was the largest during lateral bending. The endplate stress of models A and B was 150.5% and 140.9% of that of model C, respectively. The stress of the screw-rod system was the highest during lateral bending (model A, 102.0 MPa), which was 108.4%, 102.4%, 110.4%, 114.2% of model B and 158.5%, 110.1%, 115.8%, 125.4% of model C in flexion, extension, lateral bending, and rotation, respectively. Conclusions For people with osteoporosis, no matter what type of cage is used, good immediate stability can be achieved after surgery. Larger cage sizes provide better fixation without significantly increasing ROM and IDP in adjacent segments, which may contribute to the development of ASD. In addition, larger cage sizes can disperse endplate stress and reduce stress concentration, which is of positive significance in preventing cage subsidence after operation. The cage and screw rod system establish a stress conduction pathway on the spine, and a larger cage greatly enhances the stress-bearing capacity of the front column, which can better distribute the stress of the posterior spine structure and the stress borne by the posterior screw rod system, reduce the stress concentration phenomenon of the nail rod system, and avoid exceeding the yield strength of the material, resulting in the risk of future instrument failure.

ObjectiveMulti‐segmental total en bloc spondylectomy (TES) gradually became more commonly used by clinicians. However, the choice of surgical strategy is unclear. This study aims to investigate the biomechanical performance of different prosthesis types and fixation ranges in multisegmental TES.MethodsIn this study, a validated finite element model of T12–L2 post‐spondylectomy operations were carried out. The prostheses of these models used either 3D‐printed artificial vertebrae or titanium mesh cages. The fixed range was two or three segment levels. Range of motion, stress distribution of the endplate and internal fixation system, intervertebral disc pressure, and facet joint surface force of four postoperative models and intact model in flexion and extension, as well as lateral bending and rotation were analyzed and compared.ResultsThe type of prosthesis used in the anterior column reconstruction mainly affected the stress of the adjacent endplate and the prosthesis itself. The posterior fixation range had a greater influence on the overall range of motion (ROM), the ROM of the adjacent segment, the stress of the screw‐rod system, and adjacent facet joint surface force. For the model of the same prosthesis, the increase of fixed length resulted in an obvious reduction of ROM. The maximal decrease was 70.23% during extension, and the minimal decrease was 30.19% during rotation.ConclusionIn three‐segment TES, the surgical strategy of using 3D‐printed artificial prosthesis for anterior column support and pedicle screws for posterior fixation at both two upper and lower levels respectively can reduce the stress on internal fixation system, endplates, and adjacent intervertebral discs, resulting in a reduced risk of internal fixation failure, and ASD development.

Critical-sized bone defects are usually accompanied by bacterial infection leading to inflammation and bone nonunion. However, existing biodegradable materials lack long-term therapeutical effect because of their gradual degradation. Here, a degradable material with continuous ROS modulation is proposed, defined as a sonozyme due to its functions as a sonosensitizer and a nanoenzyme. Before degradation, the sonozyme can exert an effective sonodynamic antimicrobial effect through the dual active sites of MnN4 and Cu2O8. Furthermore, it can promote anti-inflammation by superoxide dismutase- and catalase-like activities. Following degradation, quercetin-metal chelation exhibits a sustaining antioxidant effect through ligand-metal charge transfer, while the released ions and quercetin also have great self-antimicrobial, osteogenic, and angiogenic effects. A rat model of infected cranial defects demonstrates the sonozyme can rapidly eliminate bacteria and promote bone regeneration. This work presents a promising approach to engineer biodegradable materials with long-time effects for infectious bone defects.

ObjectiveTo study the biomechanical characteristics of various tissue structures of different sizes of 3D printed Cage in lumbar interbody fusion.MethodsA finite element model of normal spine was reconstructed and verified. Pedicle screws and Cage of different sizes were implanted in the L4/5 segment to simulate lumbar interbody fusion. The range of motion of the fixed and cephalic adjacent segment, the stress of the screw-rod system, the stress at the interface between cage and L5 endplate, and intervertebral disc pressure of the adjacent segment were calculated and analyzed.ResultsThe range of motion and intervertebral disc pressure of the adjacent segment of each postoperative model were larger than those of the intact model, but there was not much difference between them. The stress of cage-endplate interface was also larger than that of the intact model. However, the difference is that the stress of the endplate and the screw-rod system has a tendency to decrease with the increase of the axial area of cage.ConclusionsCage with larger axial area in lumbar interbody fusion can reduce the stress of internal fixation system and endplate, but will not increase the range of motion and intervertebral disc pressure of adjacent segment. It has a certain effect in preventing the cage subsidence, internal fixation system failure and screw rod fracture.