Chengzhen Liang

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.

Mitochondrial dysfunction plays a pivotal role in intervertebral disc degeneration (IVDD) by disrupting mitochondrial bioenergetic balance, which leads to impaired ATP synthesis, accumulation of ROS, degradation of the extracellular matrix, and degeneration of nucleus pulposus cells. Despite advances in single or multiple therapeutic strategies, a more comprehensive and coupled cascade regulation strategy that fundamentally restores mitochondrial function is urgently needed, but rarely reported. Mitochondrial bioenergetics is cascade-regulated by the interplay between the OXPHOS and the TCA cycle, where impairment of either disrupts energy homeostasis, necessitating coordinated cascade therapeutic intervention. Hence, mitochondria-targeting polymeric micelles (AKG@PIDE-OPDEA) were constructed via self-assembly of an amphiphilic polymer (PIDE-OPDEA) and α-ketoglutarate (AKG). AKG@PIDE-OPDEA enabled a synergistic mitochondrial repair approach by addressing both the "raw materials" (AKG supply) and the "production line" (mitochondrial respiratory function). Through this concatenation-like therapy, AKG@PIDE-OPDEA restores the mitochondrial bioenergetics in degenerated NPCs and alleviates ECM degradation. In terms of mechanism, it restrains mitochondrial hyperfragmentation and mitigates mitochondrial matrix swelling, which effectively limit stress-induced mtDNA leakage, subsequently inhibiting cGAS-STING pathway activation and reducing downstream inflammation. Overall, this study demonstrates the feasibility of an intramitochondrial energy chain therapy, offering a novel strategy for the treatment of IVDD.

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.

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.

Circular RNAs (circRNAs) play a critical regulatory role in degenerative diseases; however, their functions and therapeutic applications in intervertebral disc degeneration (IVDD) have not been explored. Here, we identified that a novel circATXN1 highly accumulates in aging nucleus pulposus cells (NPCs) accountable for IVDD. CircATXN1 accelerates cellular senescence, disrupts extracellular matrix organization, and inhibits mitochondrial respiration. Mechanistically, circATXN1, regulated by heterogeneous nuclear ribonucleoprotein A2B1-mediated splicing circularization, promotes progerin translocation from the cell nucleus to the cytoplasm and inhibits the expression of insulin-like growth factor 1 receptor (IGF-1R). To demonstrate the therapeutic potential of circATXN1, siRNA targeting the backsplice junction of circATNX1 was screened and delivered by tetrahedral framework nucleic acids (tFNAs) due to their unique compositional and tetrahedral structural features. Our siRNA delivery system demonstrates superior abilities to transfect aging cells, clear intracellular ROS, and enhanced biological safety. Using siRNA–tFNAs to silence circATXN1, aging NPCs exhibit reduced mislocalization of progerin in the cytoplasm and up-regulation of IGF-1R, thereby demonstrating a rejuvenated cellular phenotype and improved mitochondrial function. In vivo, administering an aging cell-adapted siRNA nucleic acid framework delivery system to progerin pathologically expressed premature aging mice (zmpste24 ^−/− ) can ameliorate the cellular matrix in the nucleus pulposus tissue, effectively delaying IVDD. This study not only identified circATXN1 functioning as a cell senescence promoter in IVDD for the first time, but also successfully demonstrated its therapeutic potential via a tFNA-based siRNA delivery strategy.