Qixin Chen

Previous optogenetic bioelectronic systems have enabled a highly selective way of modulating neural populations by delivering a certain wavelength of light to engage with exogenously expressed light‐sensitive proteins, which lay the foundation of therapeutic interventions of neural circuits. However, real‐time biofeedback and strategic modulation are crucial for adjusting customized clinical treatment adjustment. To achieve this purpose, we integrated illumination, temperature, and electromyographic (EMG) sensing elements into the optogenetic bioelectronic system to avoid overexposure caused by localized overheating and to provide functional recovery evaluation during neural regeneration, which guides the in situ adjustment of the intensity, frequency, and duration of illumination parameters controlled by a wireless connected programmable external control board. In this study, both in vitro and in vivo experiments were performed to examine the optical, thermal, and electrical characteristics of our bioelectronic system. On this basis, we demonstrated a series of standardized EMG results to evaluate the recovery condition and modify the illumination parameters of each test rat. Combining temperature monitoring feedback and EMG signaling feedback, our optogenetic bioelectronic system enables strategic optogenetic spinal cord injury (SCI) treatment through real‐time illumination modulation to achieve customized spinal cord injury treatment.

The central nervous system (CNS) barrier obstructs therapeutic component entrance and hinders the therapy efficiency of CNS diseases. An ideal delivery system should penetrate and concentrate in the CNS without safety concerns. Nanovesicles (NVs) are a popular delivery tool, because of their biological homology, inherent homing effects, and capacity to penetrate barriers. However, the delivery efficacy of NVs is insufficient for CNS disease therapy, and the mechanism for barrier penetration remains elusive. Herein, nanovesicles (NVs) were extruded from mesenchymal stem cells and modified by a lesion tissue affinity peptide (CAQK) for spinal cord injury (SCI) therapy. The NVs penetrated endothelial barriers effectively in vitro. Subsequently, the CNS barrier penetration capacity of the CAQK-conjugated NVs (CNVs) was verified in vivo in spinal cord injury (SCI) and the temporary middle cerebral artery occlusion (t-MCAO) mouse models. Furthermore, the endothelial barrier penetration of CNVs depended on the active endocytosis by endothelial cells. After endocytosis, the Rab11+ endosome was identified to mediate a transcellular transcytosis to transport CNVs across the barrier. In the SCI model, CNVs promoted the lesion tissue accumulation, leading to improvement in the neural functional recovery. In summary, we developed a natural NV tool for SCI therapy, employing the inherent CNS barrier penetration capacity and enhanced lesion tissue homing characteristics of NVs. The NVs crossed the CNS barriers via active endocytosis, followed by Rab11+ endosome-mediated transcytosis. The CNV exhibited good delivery efficacy and therapeutic effects in CNS diseases and has the potential for clinical translation.

Stem cells hold great promise for repairing degenerated nucleus pulposus (NP) in intervertebral disc degeneration (IVDD) via differentiating into NP-like cells and replenishing the extracellular matrix (ECM). However, the harsh environment in degenerated NP contributes to poor survival, low differentiation efficiency, and matrix catabolism, hampering stem cells' long-term transplantation and efficacy. Herein, a hyaluronic acid (HA)-based hydrogel (Pep-aGel) functionalized with collagen mimetic peptide and amination is fabricated to deliver glycoengineered stem cells for NP repair. The peptide (GFOGER), which contains the integrin recognition sequence of collagen, is selectively bound to the upregulated integrin-β1 of glycoengineered stem cells, thereby promoting their NP-like differentiation. The amination introduced amino groups in hydrogel and further enhanced the integration of cell-secreted glycosaminoglycans (GAGs) on the HA chains, which mimicked the biosynthesis of Aggrecan, creating an NP-like nanostructure in the hydrogel. Pep-aGel loading with glycoengineered cells showed injectable properties and significantly improved disc height, extracellular matrix content, and GAG deposition in rat degenerated discs. This approach established a self-sufficient system that consists of NP cell replenishment, in situ ECM supply, and GAG anchoring, which may offer a concise, yet synergistic, strategy for the regeneration of IVDD.

Intervertebral disc degeneration (IVDD), a major contributor to chronic low back pain (LBP), involves progressive extracellular matrix (ECM) degradation and limited self‐repair. Current therapies alleviate symptoms but fail to halt degeneration, driving interest in endogenous stem cell‐based regeneration. Endogenous stem/progenitor cells within disc niches exhibit regenerative potential through ECM synthesis, anti‐inflammatory signaling, and exosomal miRNA‐mediated repair. Preclinical studies highlight mesenchymal stem cell (MSC) transplantation and reprogramed induced pluripotent stem cells (iPSCs) in restoring disc hydration and reducing pain, while early clinical trials report symptomatic relief (e.g., 70% pain reduction) but incomplete structural recovery. Challenges include the disc’s hostile microenvironment (hypoxia and nutrient deprivation), age‐related depletion of endogenous stem/progenitor cells, and impaired cell homing under mechanical stress. Emerging strategies target epigenetic modulation, biomimetic scaffolds, and combination therapies to enhance cell survival and integration. Despite promising preclinical outcomes, clinical translation requires overcoming microenvironmental barriers and refining delivery systems. Future efforts should prioritize large‐animal validation and biomarker‐guided approaches to bridge the gap between experimental success and therapeutic application.

Background: Skeleton involvement is one of the most significant aspects of Gaucher disease (GD). However, the treatment for spinal involvement in GD among patients undergoing enzyme replacement therapy (ERT) is poorly characterized. We present a case of progressive kyphotic spinal deformity in a young child caused by vertebral involvement, which was managed by posterior spinal fusion without anterior spinal release under ERT. Case presentation: This is a retrospective study. A 10-year-old boy presenting with progression kyphosis (thoracic kyphotic angle of 113°) associated with type-IIIb GD had undergone posterior spinal fusion with segmental pedicle screw fixation (from T6-L3) and Ponte osteotomy. The patient went back to school without further brace protection. Proximal junctional kyphosis (PJK) was observed at 4 months postoperatively. Revision surgery was performed to prevent neurological impairment. Additional posterior spinal fusion from T2–T6 and decompressive laminectomy were performed during the revision surgery. A 2-year follow-up showed no recurrence of PJK and solid fusion was achieved in the patient under ERT and brace protection. Conclusions: Posterior spinal fusion without anterior spinal release is a good treatment option for severe spinal deformity in patients with GD. However, the fusion level and reinforced fixation require careful consideration. Revision surgery and brace protection is needed as long as PJK is observed.

Spinal cord injuries impose a notably economic burden on society, mainly because of the severe after-effects they cause. Despite the ongoing development of various therapies for spinal cord injuries, their effectiveness remains unsatisfactory. However, a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic reprogramming. In this review, we explore the metabolic changes that occur during spinal cord injuries, their consequences, and the therapeutic tools available for metabolic reprogramming. Normal spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic coupling. However, spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism, lipid metabolism, and mitochondrial dysfunction. These metabolic disturbances lead to corresponding pathological changes, including the failure of axonal regeneration, the accumulation of scarring, and the activation of microglia. To rescue spinal cord injury at the metabolic level, potential metabolic reprogramming approaches have emerged, including replenishing metabolic substrates, reconstituting metabolic couplings, and targeting mitochondrial therapies to alter cell fate. The available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord injury. To further advance the metabolic treatment of the spinal cord injury, future efforts should focus on a deeper understanding of neurometabolism, the development of more advanced metabolomics technologies, and the design of highly effective metabolic interventions.

With a booming aging population worldwide, bone and joint degenerative diseases have gradually become a major public health focus, attracting extensive scientific attention. However, the effective treatments of these degenerative diseases have been confined to traditional medications and surgical interventions, which easily lead to the possibility of drug abuse or loss of physiological function to varying degrees. Recently, given that the development of reprogramming has overcome shackles in the field of degenerative diseases, direct reprogramming would provide a new concept to accelerate progress in the therapy of bone and joint degenerative diseases. The process of direct reprogramming would directly induce ordinary somatic cells to the desired targeted cells without passing through pluripotent cell states. In this review, we summarize some direct reprogramming of cells that has been attempted for the repair of common bone and joint degenerative diseases, such as osteoarthritis, osteoporosis-related fracture and intervertebral disc degeneration. However, it is inevitable that some obstacles, such as accurate transcription factors, an appropriate extracellular microenvironment and efficient delivery carriers in vivo, need to be resolved. In addition, developmental and promising directions associated with direct reprogramming have attracted public attention. Investigation of the regulation of the transient genome, metabolic conversion and cellular skeleton would provide superior potential candidates for the revolution of direct reprogramming. The aim of direct reprogramming is to directly provide target cells for cell therapy and even tissue reconstruction in bone and joint degenerative diseases. Moreover, the development of direct reprogramming have potential to achieve repair and even reconstruct in situ, which would be breakthrough effect for the repair of bone and joint degenerative diseases. The advance of direct reprogramming has opened numerous opportunities for new therapeutic strategies in regenerative medicine.

Spinal cord injury (SCI) causes blood‐spinal cord barrier (BSCB) disruption, leading to secondary damage, such as hemorrhagic infiltration, inflammatory response, and neuronal cell death. It is of great significance to rebuild the BSCB at the early stage of SCI to alleviate the secondary injury for better prognosis. Yet, current research involved in the reconstruction of BSCB is insufficient. Accordingly, we provide a thermosensitive hydrogel‐based G protein‐coupled receptor 124 (GPR124) delivery strategy for rebuilding BSCB. Herein, we firstly found that the expression of GPR124 decreased post‐SCI and demonstrated that treatment with recombinant GPR124 could partially alleviate the disruption of BSCB post‐SCI by restoring tight junctions (TJs) and promoting migration and tube formation of endothelial cells. Interestingly, GPR124 could also boost the energy metabolism of endothelial cells. However, the absence of physicochemical stability restricted the wide usage of GPR124. Hence, we fabricated a thermosensitive heparin‐poloxamer (HP) hydrogel that demonstrated sustained GPR124 production and maintained the bioactivity of GPR124 (HP@124) for rebuilding the BSCB and eventually enhancing functional motor recovery post‐SCI. HP@124 hydrogel can encapsulate GPR124 at the lesion site by injection, providing prolonged release, preserving wounded tissues, and filling injured tissue cavities. Consequently, it induces synergistically efficient integrated regulation by blocking BSCB rupture, decreasing fibrotic scar formation, minimizing inflammatory response, boosting remyelination, and regenerating axons. Mechanistically, giving GPR124 activates energy metabolism via elevating the expression of phosphoenolpyruvate carboxykinase 2 (PCK2), and eventually restores the poor state of endothelial cells. This research demonstrated that early intervention by combining GPR124 with bioactive multifunctional hydrogel may have tremendous promise for restoring locomotor recovery in patients with central nervous system disorders, in addition to a translational approach for the medical therapy of SCI.