The emergence of multi‐drug resistant (MDR) pathogens is a major public health concern, posing a substantial global economic burden. Photothermal therapy (PTT) at mild temperature presents a promising alternative to traditional antibiotics due to its biological safety and ability to circumvent drug resistance. However, the efficacy of mild PTT is limited by bacterial thermotolerance. Herein, a nanocomposite, BP@Mn‐NC, comprising black phosphorus nanosheets and a manganese‐based nanozyme (Mn‐NZ) is developed, which possesses both photothermal and catalytic properties. Mn‐NZ imparts glucose oxidase‐ and peroxidase‐like properties to BP@Mn‐NC, generating reactive oxygen species (ROS) that induce lipid peroxidation and malondialdehyde accumulation across the bacterial cell membrane. This process disrupts unprotected respiratory chain complexes exposed on the bacterial cell membrane, leading to a reduction in the intracellular adenosine triphosphate (ATP) content. Consequently, mild PTT mediated by BP@Mn‐NC effectively eliminates MDR infections by specifically impairing bacterial thermotolerance because of the dependence of bacterial heat shock proteins (HSPs) on ATP molecules for their proper functioning. This study paves the way for the development of a novel photothermal strategy to eradicate MDR pathogens, which targets bacterial HSPs through ROS‐mediated inhibition of bacterial respiratory chain activity.

Complicated peripheral nerve injuries or defects, especially at branching sites, remain a prominent clinical challenge after the application of different treatment strategies. Current nerve grafts fail to match the expected shape and size for delicate and precise branched nerve repair on a case-by-case basis, and there is a lack of geometrical and microscale regenerative navigation. In this study, we develop a sugar painting-inspired individualized multilevel epi-/peri-/endoneurium-mimetic device (SpinMed) to customize natural cues, featuring a selectively protective outer sheath and an instructive core, to support rapid vascular reconstruction and consequent efficient neurite extension along the defect area. The biomimetic perineurium dictates host-guest crosslinking in which new vessels secrete multimerin 1 binding to the fibroin filler surface as an anchor, contributing to the biological endoneurium that promotes Schwann cell homing and remyelination. SpinMed implantation into rat sciatic nerve defects yields a satisfactory outcome in terms of structural reconstruction, with sensory and locomotive function restoration. We further customize SpinMed grafts based on anatomy and digital imaging, achieving rapid repair of the nerve trunk and branches superior to that achieved by autografts and decellularized grafts in a specific beagle nerve defect model, with reliable biosafety. Overall, this intelligent art-inspired biomimetic design offers a facile way to customize sophisticated high-performance nerve grafts and holds great potential for application in translational regenerative medicine.

The Ilizarov technique has been continuously innovated to utilize tensile stress (TS) for inducing a bone development‐like regenerative process, aiming to achieve skeletal elongation and reconstruction. However, it remains uncertain whether this distraction osteogenesis (DO) process induced by TS involves the pivotal coupling of angiogenesis and osteogenesis mediated by type H endothelial cells (THECs). In this study, it is demonstrated that the Ilizarov technique induces the formation of a metaphysis‐like architecture composed of THECs, leading to segmental bone regeneration during the DO process. Mechanistically, cell‐matrix interactions‐mediated activation of yes‐associated protein (YAP)/transcriptional co‐activator with PDZ‐binding motif (TAZ) transcriptionally upregulates the expression of Notch1 and Delta‐like ligand 4, which act as direct positive regulators of THECs phenotype, in bone marrow endothelial cells (BMECs) upon TS stimulation. Simultaneously, the Notch intracellular domain enhances YAP/TAZ activity by transcriptionally upregulating YAP expression and stabilizing TAZ protein, thus establishing the YAP/TAZ‐Notch circuit. Additionally, TS‐stimulated BMECs secrete exosomes enriched with vital molecules in this positive feedback pathway, which can be utilized to promote segmental bone defect healing, mimicking the therapeutic effects of Ilizarov technique. The findings advance the understanding of TS‐induced segmental bone regeneration and establish the foundation for innovative biological therapeutic strategies aimed at activating THECs.

Osteoarthritis (OA) is a common degenerative joint disease which currently lacks of effective agents. It is therefore urgent and necessary to seek an effective approach that can inhibit inflammation and promote cartilage matrix homeostasis. Cartilage progenitor cells (CPCs) are identified as a cell population of superficial zone in articular cartilage which possess strong migration ability, proliferative capacity, and chondrogenic potential. Recently, the application of CPCs may represent a novel cell therapy strategy for OA treatment. There is growing evidence that extracellular vesicles (EVs) are primary mediators of the benefits of stem cell-based therapy. In this study, we explored the protective effects of CPCs-derived EVs (CPCs-EVs) on IL-1β-induced chondrocytes. We found CPCs-EVs exhibited chondro-protective effects in vitro. Furthermore, our study demonstrated that CPCs-EVs promoted matrix anabolism and inhibited inflammatory response at least partially via blocking STAT3 activation. In addition, liquid chromatography-tandem mass spectrometry analysis identified 991 proteins encapsulated in CPCs-EVs. By bioinformatics analysis, we showed that STAT3 regulatory proteins were enriched in CPCs-EVs and could be transported to chondrocytes. To promoting the protective function of CPCs-EVs in vivo, CPCs-EVs were modified with cationic peptide ε-polylysine-polyethylene-distearyl phosphatidylethanolamine (PPD) for surface charge reverse. In posttraumatic OA mice, our results showed PPD modified CPCs-EVs (PPD-EVs) effectively inhibited extracellular matrix catabolism and attenuated cartilage degeneration. Moreover, PPD-EVs down-regulated inflammatory factors expressions and reduced OA-related pain in OA mice. In ex-vivo cultured OA cartilage explants, PPD-EVs successfully promoted matrix anabolism and inhibited inflammation. Collectively, CPCs-EVs-based cell-free therapy is a promising strategy for OA treatment.

Background: Limited stem cells, low vascularization efficiency, and weak osteoinductive activity plague the repair and reconstruction of bone defects with cell-free scaffolds. Methods: Herein, injectable platelet-rich fibrin (i-PRF) was loaded into a alginate methacryloyl (AlgMA)/gelatin methacryloyl (GelMA)-methylcellulose (AGM) bioink system and constructed a porous hydrogel scaffold by 3D bioprinting. The addition of nanosilicate-laponite (Lap) further enhanced this scaffold and synergized with i-PRF to promote efficient and personalized cranial regeneration. Results: At the biochemical level, Lap significantly enhanced the ability of the scaffold to retard growth factor release, and multiple physiologically proportional growth factors in the scaffold synergistically promoted rapid neoangiogenesis and concomitantly recruited endogenous bone marrow mesenchymal stem cells (BMSCs). More importantly, the bioactive ions released by Lap markedly promoted the proliferation of BMSCs and consistently induced the osteogenic differentiation of BMSCs. At the immunological level, i-PRF-AGM@Lap significantly attenuates the inflammatory response by promoting macrophage M2 polarization. Mechanistically, miRNA sequencing and functional validation experiments demonstrated that bioactive ions released by Lap could synergize with growth factors in i-PRF to promote osteogenic differentiation of BMSCs through the miR-21 and miR-125a-mediated transforming growth factor-β/Smads signaling pathway. Conclusion: The results of this study provide a new idea for the personalized treatment of bone defects.

Osteonecrosis of the femoral head (ONFH) represents a severe complication of glucocorticoids (GCs) therapy in clinical settings. MicroRNAs (miRNAs) are critically involved in the progression of GCs-induced ONFH, with ferroptosis playing a central role in its pathology. However, the regulatory effects of specific miRNAs targeting ferroptosis in ONFH have not been previously explored. The aim of this study was to elucidate the effect and the specific molecular mechanisms of miR-370-3p in the progression of GCs-induced ONFH. In this study, we first established a rat model of GCs-induced ONFH and analyzed changes in osteogenesis and ferroptosis. Subsequently, we performed miRNA sequencing on bone marrow-derived mesenchymal stem cells (BMSCs) after dexamethasone treatment. In vitro, we assessed the effects of miR-370-3p on cell proliferation, osteogenic activities, and ferroptosis in BMSCs. We used dual luciferase assays to identify the target gene of miR-370-3p, examining its regulatory effects on osteogenesis and ferroptosis. In vivo, we estimated the effect of miR-370-3p on the femoral head by isolating exosomes from BMSCs overexpressing miR-370-3p and administering them to rats. We observed that impaired osteogenesis and enhanced ferroptosis are principal pathogenic factors in the progression of GCs-induced ONFH. We identified miR-370-3p as a significant regulatory element in bone marrow-derived mesenchymal stem cells (BMSCs) through miRNA sequencing following GCs treatment. Moreover, miR-370-3p could protect BMSCs viability against GCs impairment in vitro and enhance Ki67 expression in the femoral head. The osteogenic capacity of BMSCs was strengthened by miR-370-3p under GCs condition. In addition, miR-370-3p was found to reduce ferroptosis activities, including iron overload and lipid peroxidation. Mechanically, we found that toll-like receptor 4 (TLR4) was the target of miR-370-3p. And miR-370-3p could exert critical regulatory effects by targeting TLR4/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) axis under GCs intervention. Importantly, inhibition of ferroptosis partially restored osteogenic capacity of BMSCs in vitro. In a rat model of GCs-induced ONFH, miR-370-3p played a critical protective role in the femoral head by enhancing osteogenesis and inhibiting ferroptosis. miR-370-3p could regulate the changes in osteogenesis and ferroptosis in the progression of GCs-induced ONFH through targeting TLR4/SLC7A11/GPX4 axis. This study is the first to unveil the regulatory interaction between miRNA and ferroptosis in GC-induced ONFH, providing valuable insights into its pathogenesis and identifying potential therapeutic targets.