Background: Osteoarthritis (OA) characterized by progressive cartilage degeneration and chronic pain is hindered by the vicious inflammation-pain cycle. Nonsteroidal anti-inflammatory drugs (NSAIDs) can only alleviate clinical symptoms. Although electrical stimulation of the vagus nerve has achieved some results, the toxicity of the electrodes and the secondary damage caused by dismantling limited its clinical application. Methods: A "sono-piezoelectric-bioelectricity-neuroimmune" cascade modulation strategy based on ultrasound-driven piezoelectric ZnO nanoparticles was established to attenuate osteoarthritic neurogenic inflammation and pain with inhibited cartilage degradation. Results: The "sensory neuron-cholinergic anti-inflammatory pathway" reflex arc was activated by the dynamically and spatially-temporally programmed sono-piezoelectric field (0.7 V/36 μA peak) within deep joint tissues by targeting α7nAChR-P2RX7 neuroimmune axis. Consequently, our sono-piezoelectric neuroimmune modulation strategy significantly up-regulated α7nAChR expression, and synchronously inhibited pain mediator CX3CL1, opposed macrophage infiltration, inhibited P2RX7-mediated IL-1β/IL-6 inflammatory storm, restored IL-1β-injured chondrocyte activity and migration capacity, activated stromal genes (Col2a1) for matrix synthesis, and inhibited cartilage degradation-related MMP13 expression. All these actions re-established the balance of glycosaminoglycan (GAG)/deoxyribonucleic acid (DNA) metabolism to remodel joint immune homeostasis, and activated the cholinergic pathway to break the vicious cycle of "inflammation-pain", which restored mechanical pain threshold (Von Frey) and weight-bearing capacity to near-normal levels and reconstructed tidal structures in a rat OA model. Conclusions: Our pioneering "sono-piezoelectrical signal-neural reflex-immunomodulation" cascade strategy for regulating neuroinflammatory reflex-arc-mediated α7nAChR-P2RX7 axis provide deep insights into OA-represented neuroinflammatory diseases.

Photoaffinity Labeling-Affinity-Based Protein Profiling (PAL-AfBPP) provides breakthrough solutions in a variety of fields such as target protein discovery. The selection of photoaffinity connectors is the key component of PAL-AfBPP probe design and application. At present, the development of organic chemistry has also made the thiophene-substituted α-ketoamide, tetrazole, isoxazole, 2-nitrobenzyl alcohol and other structures become new photoaffinity ligand candidates for the design of PAL-AfBPP probes. However, how the conjugation of different linkers with active molecules affects the biological activity, labeling efficiency, and target preference of the parent compounds remains unclear. The previous study found that the active quinazolinone molecules represented by QDAU5 had significant vascular normalizing effect, and finally identified that EphrinB2 was an intracellular target protein of QDAU5. At the same time, it was also found that thymosinβ4 (Tβ4) was effectively enriched by QDAU5 probe, which may be another way for QDAU5 to exert biological effects. Herein, we constructed a photocrosslinker library and a multifunctional photoaffinity probe library to verify the effects of different photocrosslinkers on the activity and labeling preference of quinazolinones. Based on proteomic analysis, the potential target Tβ4 was further validated, and the interaction mode between QDAU5 and Tβ4 was preliminarily elucidated. The results of this study provide a practical reference for the precise selection of photocrosslinkers in PAL-AfBPP probe design, and also provide more support for elucidating the mechanism of angiogenesis regulation and vascular normalization by active quinazolinones.

Posterior segment eye diseases (PSEDs) remain a leading cause of irreversible blindness, with the eye's dynamic and static barriers posing challenges to effective drug delivery through different administration routes. Currently, treatment options available for PSEDs are limited, with invasive intravitreal injection being the predominant choice. However, frequent injections carry a high risk of complications, and are associated with low patient compliance. The rapid advancement of nanomaterials has sparked intense interest in nanoconstructed drug delivery systems as potential solutions to overcome these bottlenecks. Experimental studies have demonstrated that diverse nanocarriers can accommodate different therapeutic agents and circumvent ocular barriers through multiple mechanisms, including prolonged drug residence, enhanced tissue permeability, to name a few. In addition, nanomaterial‐based delivery systems also offer advantages in improving posterior segment drug delivery efficiency and therapeutic practicality. In this review, the multiple ocular barriers and traditional administration routes are presented first. Then, we focus on the promise held by nanoplatforms for barrier penetration and summarize key mechanisms involved. Meanwhile, the review highlights the value of nanocarriers in achieving efficient drug delivery and treatment of PSEDs with illustrative examples and tables. Finally, current challenges and future prospects are also discussed here to encourage basic research and clinical transformation.

Conventional transarterial chemoembolization (TACE) regimens for hepatocellular carcinoma (HCC) are often compromised in efficacy due to hypoxia and acidosis within the tumor microenvironment (TME), frequently leading to unsatisfactory treatment outcomes and tumor recurrence. To overcome these limitations, this study introduces an innovative approach by incorporating a hydrogen generator (calcium hydride, CaH₂) into an epirubicin (EPI)-iodized oil embolization system. This design enables local hydrogen release to remodel the TME following TACE, thereby enhancing the combined chemo-immunotherapeutic antitumor response. Nano-CaH₂ particles, co-delivered locally via TACE, undergo hydrolysis to continuously release hydrogen gas (H₂) and calcium ions (Ca2+). This reaction disrupts mitochondrial function in cancer cells, reduces oxygen consumption, alleviates tumor hypoxia, and consequently counteracts chemoresistance. Simultaneously, EPI induces immunogenic cell death (ICD) in moribund tumor cells, activating the host's antitumor immune response. Additionally, the hydroxide ions generated from CaH₂ hydrolysis neutralize the acidic TME, alleviating immunosuppression and further amplifying the chemo-immunotherapeutic synergy mediated by TACE. This strategy presents a novel method to improve TACE efficacy and facilitate its integration with immunotherapy, demonstrating considerable potential for clinical translation.

Hepatocellular carcinoma (HCC) relapse following incomplete microwave ablation (iMWA) represents a formidable clinical challenge. This progression is fueled by residual tumor cells that exhibit cell death resistance and dysregulated fatty acid metabolism, while exploiting a myeloid-derived immunosuppressive microenvironment. To address this limitation, we developed an injectable binary-amplified cascade hydrogel (S/CuCo@HD) that co-delivers CD36 inhibitor sulfosuccinimidyl oleate (SSO) and a copper-cobalt bimetal-organic framework (Cu-Co BMF). Locally administered S/CuCo@HD serves as a reservoir for sustained-release SSO and Cu-Co BMF within tumor cavities post-iMWA, provoking self-reinforced lipid oxygen radical storm by collaborative SSO-mediated fatty acid composition rewiring and peroxidase-mimetic Cu-Co BMF catalysis. The binary amplified radical reaction together with Cu2+-triggered cuproptosis culminates in a binary-amplified mitochondria crisis and subsequent the cytosolic release of damaged DNA fragments. Critically, these danger signals function as a pivotal immunological switch, sequentially initiating binary-amplified STING activation with Co2+ potentiation while simultaneously inducing robust ICD. The consequent release of damage-associated molecular patterns and interferon-β promotes dendritic cell maturation, polarizes macrophages toward an M1 phenotype, and facilitates T-cell infiltration, ultimately reprogramming the immunosuppressive microenvironment into an immune-activated niche. Crucially, S/CuCo@HD synergizes with anti-PD-1 therapy to reinvigorate cytotoxic T lymphocytes and establish durable immune memory, effectively suppressing tumor relapse and metastasis post-iMWA, offering an integrated metallo-metabolic-immunomodulation strategy with promising translational potential for comprehensive HCC management.

177Lu has attracted substantial attention in recent years as a medical radionuclide. It emits both β-particles (maximum energy 0.497 MeV) and γ-rays (113/208 keV), which provides unique advantages for theranostic applications in oncology. Since the U.S. Food and Drug Administration (FDA) approved [177Lu]Lu-DOTA-TATE in 2018, 177Lu-based radiopharmaceuticals have demonstrated significant clinical value in the targeted treatment of neuroendocrine tumors (NETs) and prostate cancer. However, monotherapy still faces major challenges, including tumor heterogeneity, drug resistance, and dose-related toxicity. These limitations hinder the full therapeutic potential of 177Lu radiopharmaceuticals. Combination therapy has therefore emerged as a promising strategy to address these obstacles. This review provides a systematic overview of the preparation techniques, clinical efficacy, and combination therapy approaches involving 177Lu radiopharmaceuticals, with the aim of offering a theoretical foundation and practical guidance for optimizing therapeutic paradigms.

Emerging evidence suggests dietary interventions regulate inflammatory signaling through gut microbiome modulation, yet their therapeutic potential in radiation-induced intestinal injury (RIII) remains underexplored. This study demonstrates that ketogenic diet (KD), a high-fat and low-carbohydrate dietary regimen, exerts protective effects against RIII through dual mechanisms involving microbial regulation and inflammatory pathway inhibition. Using high-salt diet (HSD) as a dietary control, KD significantly attenuated intestinal inflammation by downregulating pro-inflammatory cytokines while enhancing barrier integrity through tight junction protein upregulation in radiation-exposed murine model. 16S rDNA sequencing showed KD enriched Akkermansia and reduced Enterobacteriaceae, whereas HSD exhibited inverse patterns. Mechanistically, RNA sequencing revealed that KD uniquely suppressed the JAK2/STAT3 pathway in RIII mice. In vitro studies demonstrated that β-hydroxybutyrate, a key ketone metabolite, effectively suppressed RORγt expression and subsequent downregulation of IL-17A gene transcription via the inhibition of JAK2/STAT3 pathway, thus mitigate inflammatory damage. Fecal microbiota transplantation validated that KD-modified microbiome directly inhibited JAK2/STAT3 signaling activation, as well as the downregulation of RORγt and IL-17A. These findings establish KD as a promising dietary strategy mitigate acute RIII through synergistic modulation of gut microbiota and inflammatory signaling, providing novel insights into nutritional approaches targeting microbial-host crosstalk in radiation injury.

Calvarial defect repair is frequently limited by immune dysregulation and insufficient coupling with bone regeneration. This study investigated the regulatory role of reticulocalbin-2 (RCN2) in macrophages and evaluated a biomimetic periosteum-bone bilayer scaffold (PB-BLS) designed to deliver RCN2-modified M2 macrophage-derived exosomes (RCN2-Exos). A photocrosslinkable periosteum-like hydrogel was prepared from decellularized periosteal matrix (DPM), methacrylic anhydride-modified DPM, and gelatin methacryloyl (GelMA), and was loaded with RCN2-Exos. A zinc-substituted tricalcium phosphate (Zn-TCP)/chitosan (CS) bone-like scaffold was fabricated by three-dimensional printing and integrated with the periosteum-like layer to form PB-BLS. Material characterization confirmed favorable mechanical properties and controllable exosome release. In vivo studies using calvarial defect models and RCN2-knockout controls showed that RCN2 deficiency impaired bone repair and aggravated inflammatory responses. PB-BLS promoted M2 macrophage polarization, enhanced skeletal stem cell (SSC) migration and osteogenic differentiation in vitro, and significantly increased bone volume fraction (BV/TV) and bone mineral density (BMD) in vivo. Single-cell RNA sequencing and cell-cell communication analyses indicated that PB-BLS remodeled the local immuno-osteogenic microenvironment and enhanced key signaling axes, including SPP1-CD44 and CXCL12-CXCR4. These findings identify RCN2 as a pivotal mediator linking macrophage immune phenotype with osteogenic fate and support RCN2-Exos-loaded PB-BLS as a promising strategy for bone defect repair.

Chimeric antigen receptor (CAR)-T-cell therapies have displayed breakthrough efficacy in hematological oncology treatments but face challenges of off-target toxicity, immunosuppressive microenvironment and manufacturing complexity in solid tumors. Nanotechnology and nanobiotechnology empower them to overcome these bottlenecks with its unique targeting, regulation and programmability. In this review, we explored the current advances and mechanisms of nano-/nanobio-technology-enhanced CAR-T therapy in three areas of genetic, chemical and tissue engineering. The genetic engineering constructs multifunctional protein circuits by optimizing signal transduction networks. The chemical programming strategy endows spatial-temporally controlled precision regulation. Meanwhile, the organismic tissue engineering breaks through the barrier of physical delivery with the help of biomimetic microenvironmental reconfiguration. This interdisciplinary integration not only significantly enhances the infiltration capacity and persistence of CAR-T cells, but also promotes the strategic transformation of the therapeutic paradigm from “single elimination” to a spatiotemporally controlled, multimodal treatment regimen. This shift is enabled by synthetic biology circuits, bio-orthogonal chemical switches, and biomimetic tissue scaffolds that allow CAR-T cells to dynamically sense and adapt to the tumor microenvironment, providing theoretical breakthroughs and technological innovations for the treatment of solid tumors. Finally, we conclude that the deep integration of dynamic closed-loop regulatory systems with synthetic life engineering will reshape the future landscape of precision immunotherapy.

RATIONALE AND OBJECTIVES:Multiple approaches are available for defining the tibial anatomical axis when measuring the posterior tibial slope (PTS) with MRI. This study aims to evaluate the reliability of PTS measurements on MRI when the anatomical axis is defined at different tibial levels. MATERIALS AND METHODS:This study included 103 patients who underwent two distinct MRI examinations of the same knee between 2018 and 2023, with each pair of scans performed within a one-year interval and without significant morphological changes. Two anatomical axes were defined: one below the tibial plateau and another below the tibial tuberosity. The medial and lateral posterior tibial slopes (MPTS and LPTS) were measured relative to each axis. Reliability was evaluated by assessing inter-scan (test-retest), intra-rater, and inter-rater agreement. Variability between scans was further examined using Bland-Altman limits of agreement (LOA). RESULTS:Defining the anatomical axis below the tibial plateau resulted in only moderate inter-scan agreement (MPTS: ICC = 0.651; LPTS: ICC = 0.618), whereas defining it below the tibial tuberosity yielded good agreement (MPTS: ICC = 0.864; LPTS: ICC = 0.852). The 95% LOA between scans for MPTS were -6.8° to 6.4° with the plateau-based axis and -4.4° to 4.8° with the tuberosity-based axis, while those for LPTS were -6.4° to 6.5° and -4.6° to 4.5°, respectively. Both definitions of the axis demonstrated good to excellent intra- and inter-rater reliability for MPTS and LPTS measurements. CONCLUSION:Defining the anatomical axis below the tibial tuberosity yields more reliable PTS measurements, with better inter-scan agreement and good intra- and inter-rater agreement.

INTRODUCTION:Long proximal femoral intramedullary nails present challenges in the treatment of subtrochanteric fractures. Short nails may represent a suitable alternative; however, conventional preoperative planning has limitations in evaluating their appropriateness. This study investigated whether computer-assisted virtual planning can enhance implant selection consistency, short nail utilisation, and surgical outcomes. METHODS:This retrospective cohort study analysed 103 patients (57 virtual planning, 46 conventional planning) treated with proximal femoral intramedullary nailing at a Level I trauma centre in China between 2009 and 2018. Conventional planning relied on imaging and surgeon experience. Virtual planning used three-dimensional computed tomography reconstruction to simulate fracture reduction and determine optimal implant dimensions. Primary outcomes were the planned and actual implant dimensions selected. Secondary outcomes included operative parameters, complications, implant-associated adverse events, and functional scores at 12 months. Robust multivariate analysis of covariance and logistic regression analyses were performed. RESULTS:Compared with conventional planning, virtual planning demonstrated higher consistency between planned and actual short/long nail selection (kappa coefficient=0.95 vs 0.54) and implant dimensions (intraclass correlation coefficient=0.889-0.971 vs 0.786-0.870), with a higher actual short nail utilisation rate (75.4% vs 52.2%). Virtual planning reduced operative duration (90.21 vs 141.67 minutes; P<0.001), closed reduction duration (23.02 vs 30.43 minutes; P<0.001), blood loss (203.51 vs 294.78 mL; P<0.001), and number of fluoroscopy exposures (19.95 vs 29.67; P<0.001), and was associated with faster learning curves. Complications and functional scores were statistically similar between groups but numerically favoured the virtual planning group. CONCLUSION:Virtual planning improved implant selection consistency, short nail utilisation, and surgical efficiency. It demonstrated numerically superior clinical outcomes.

A dual-sided interfacial anchoring strategy suppresses buried-interface delamination, strengthens perovskite/TCO adhesion, and improves the operational stability of inverted perovskite solar cells.

Currently, the elimination of postsurgical osteosarcoma (OS) and defect repair are still separately explored, which is unlike real-world clinical scenarios. Inadequate bone marrow stromal cells (BMSCs) compromise their repair and antitumor efficiencies. Here, PFSSTKT (PFS)-functionalized KLD-12 peptide hydrogels (KLD-PFS) have been engineered and integrated with 2D BiOIO3 nanosheets to obtain the injectable sono-piezoelectric/pyroelectric peptide hydrogels (KLD-PFS@BiOIO3) featuring a supramolecular peptide nanofiber (SMPNF) structure. Differing from the dominant BaTiO3 in sono-piezoelectric dynamic therapy (SPDT) of cancer, BiOIO3 nanosheets can produce ROS through sono-piezoelectric and pyroelectric catalytic processes under ultrasound irradiation, thus enabling the combination of SPDT with pyroelectric dynamic therapy against residual OS. More significantly, PFS as a bone marrow homing peptide enables KLD-PFS to capture and recruit more BMSCs, and the inherent SMPNF structure, direct ultrasound-induced current stimuli, sono-piezoelectricity/pyroelectricity-induced current stimuli and ROS birth expedite BMSCs differentiation and bone regeneration. These multifaceted actions follow the signaling pathways associated with calcium flux and cancer-neuron communication disruptions and metabolic dysfunction rectification. They have been successfully validated to repress residual OS and favor bone regeneration in a clinical scenarios-matched postsurgical osteosarcoma and bone defect model. This study offers a promising strategy for comprehensive osteosarcoma management.

Degenerative lumbar spondylolisthesis often leads to bilateral spinal canal and intervertebral foramen stenosis, yet symptoms frequently present unilaterally. The need for decompression on the asymptomatic or mildly symptomatic side remains a topic of debate. There were 28 patients with single-level degenerative lumbar spondylolisthesis (Meyerding grades I/II) with bilateral symptoms were selected for this study. We measured preoperative and postoperative foramen height (FH), foraminal area (FA), disc height (DH), cross-sectional area of spinal canal(CASC), and degree of upper vertebral slip (DUVS). Clinical outcomes were assessed using the visual analog scale (VAS), Oswestry Disability Index (ODI), and the Macnab standard was used to evaluate the efficacy at the last postoperative follow-up. All parameters on the surgical side and the contralateral side presented a significant increase compared to preoperative values (P < 0.001). The postoperative values for FH on operative and contralateral sides were 18.13 ± 1.19 mm and 18.49 ± 1.09 mm, for FA were 120.04 ± 23.57 mm2 and 123.07 ± 21.51 mm2, for DH were 8.53 ± 0.77 mm, and the cross-sectional area of spinal canal were 117.29 ± 16.832. The VAS scores and ODI scores for lumbar pain and bilateral leg pain improved significantly. Satisfactory ipsilateral direct and contralateral indirect decompression can be achieved by unilateral-approach RA-ULIF.Routine decompression on the contralateral side may not be necessary for patients with bilateral symptoms and bilateral intervertebral foramen stenosis in single-level lumbar spondylolisthesis, barring cases of severe spinal stenosis.

BACKGROUND:Lipid metabolic reprogramming has been increasingly recognized as a key factor contributing to tumor immune evasion, therapeutic resistance, and plasticity, which collectively compromise the efficacy of targeted radionuclide therapy (TRT). Overcoming the immunosuppressive and hypoxic tumor microenvironment (TME) while interfering with tumor lipid metabolism may offer a promising strategy to potentiate TRT outcomes. METHODS:In this report, a radiopharmaceutical with multienzymatic catalysis activities is developed, wherein tumor cell membrane-coated manganese single-atom nanozymes (Mn/SAE@M) as supports deliver iodine-131 (131I) to the tumor. The Mn/SAE nanozyme core was synthesized in situ within hollow mesoporous zeolitic imidazolate frame-8 (ZIF-8) nanoparticles, then coated with homologous tumor cell membranes for targeted delivery and subsequently labeled with 131I using the Chloramine-T method. A series of in vitro and in vivo experiments was performed in non-small cell lung cancer (NSCLC) models to evaluate therapeutic efficacy and immune activation. RESULTS:131I-Mn/SAE@M exhibited efficient tumor targeting and internalization mediated by membrane camouflage. Within the TME, the radiopharmaceuticals initiated abundant oxygen (O2) release through catalase (CAT)-like catalysis, thereby mitigating a hypoxic microenvironment. In particular, it produced and enriched more reactive oxygen species (ROS) through oxidase (OXD)-, peroxidase (POD)-, and glutathione oxidase (GSHOx)-like catalytic processes. Importantly, 131I-Mn/SAE@M activated the cGAS-STING pathway, interfered with the lipid metabolic homeostasis of tumor cells, and induced ferroptosis, which is unraveled to take responsibility for the potentiated antitumor immunity. In bilateral NSCLC tumor-bearing mice, the treatment suppressed both the first and the second tumors, indicating the generation of systemic antitumor immune responses and immunological memory. CONCLUSIONS:Such SAE-based radiopharmaceuticals provide a candidate platform to elevate TRT efficiency, and the proof-of-concept rationale of disrupting lipid metabolic homeostasis through multienzyme-mimicking cascade reactions also provides a general avenue to improve TRT and synergistically magnify antitumor immunity.

Simultaneous management of intestinal mucosal barrier dysfunction and gut microbiota dysregulation represents a significant challenge in the treatment of inflammatory bowel disease (IBD). Herein, we report a novel system that integrates multi-enzyme mimicking cerium single-atom nanocatalysts (CeSACs) with Lactobacillus reuteri probiotics (LR@CeSACs) for multipronged management of IBD. In this system, CeSACs demonstrate robust multi-enzyme activities across a broad pH range, effectively scavenging elevated reactive oxygen species, downregulating pro-inflammatory cytokines, and suppressing the expression of fibrosis-related genes. Moreover, probiotics promote the targeting and retention of the CeSACs for sustained catalytic antioxidant therapy. In turn, the inflammation relief enabled by CeSACs promotes bacterial viability, allowing for the rapid reshaping of intestinal barrier function and the restoration of gut microbiota. Therefore, LR@CeSACs exhibit excellent catalytic anti-inflammatory and anti-fibrotic therapeutic effects, as well as a certain prophylactic effect, as demonstrated in several murine models.

Post-transcriptional epigenetic modifications provide numerous implications for tumor progression, metastasis and recurrence, which also pose resistances to reactive oxygen species (ROS)-based anti-tumor. Herein, we proposed an epigenetic deubiquitination disruption strategy to disarm the ubiquitination-deubiquitination balance-induced resistances to ROS production and ROS-based anti-tumor action for potentiating sonodynamic treatment (SDT) efficiency. To end it, porphyrin-derived metal-organic framework (MOF) sonocatalytic nanoplatforms were developed to load deubiquitination inhibitors (i.e., Auranofin). Ultrasound-triggered Auranofin release from PCN224@Au has been validated to blockade the deubiquitinating process and drive proteasome-mediated target protein degradation. The epigenetic deubiquitination disruption not only synergized with MOF-mediated sonocatalytic ROS production, but also inactivate deubiquitinating enzymes, blockade the deubiquitination process and further remove these resistances, both of which mutually behaved as reciprocal impetuses to significantly magnify SDT outcomes against liver cancers. Such a deubiquitination-engineered disruption approach finds an unprecedented pathway to disarm deubiquitination-induced resistances to SDT and other ROS-based anti-tumor means, which also enlightens us to establish other post-transcriptional epigenetic modification disruption strategies to re-program the tumor microenvironment and elevate the anti-tumor efficiency of various treatment methods (e.g., immunotherapy).