Dynamic alterations in metal ion concentrations are observed in the pathological process of spinal cord injury (SCI). Hence, strategically supplying metal ions in a phase-adapted manner is promising to facilitate injured spinal cord repair by preventing pathological damage. To achieve this, a chimeric hydrogel microsphere with Mg2+-crosslinked methacrylate gelatin as the "shell" and Zn2+-loaded poly (lactic-co-glycolic acid) (PLGA) as the "core" was designed. The chimeric microspheres allow continuous delivery of Mg2+ or Zn2+ at the exact required phase in SCI pathological process. Early release of Mg2+ reduced inflammation by diminishing the secretion of proinflammatory cytokines due to changes in macrophage polarization, which further suppressed scar formation to create an ideal space for neural regeneration. The subsequently released Zn2+ at the late phase effectively promoted neural cell proliferation and regeneration, which was accompanied by activation of mature neurons, interneurons, and motor neurons, leading to significant behavioral recovery. Thus, this study underscores the critical role of metal ions at different phases of injured spinal cord repair and describes the construction of an injectable chimeric hydrogel microsphere carrying distinct metal ions with a core-shell structure. Chimeric microspheres overcome the discrepancy between the inflammatory response and neural regeneration and are a promising therapeutic strategy for injured spinal cord repair.

Delayed diabetic wound healing is partially attributed to the functional disorder of skin repair cells caused by high glucose (HG). Small extracellular vehicles (sEVs) loaded with small-molecule drugs represent a highly promising therapeutic strategy. This study aims to evaluate the therapeutic efficacy of ellagic acid-encapsulated small extracellular vesicles (EA-sEVs) in diabetic wound regeneration and to unravel related mechanisms. Cytotoxicity tests of ellagic acid (EA) as liposomal small molecules (LSMs) were performed with the CCK8 assay. EA was incorporated into sEVs obtained from chorionic plate-mesenchymal stem cells (CP-MSCs) to construct EA-engineered sEVs. The protective effects of EA-sEVs on human dermal fibroblasts (HDFs) and human epidermal keratinocytes (HEKs) induced by high glucose (HG) were assessed through the evaluation of their proliferative, migrative and differentiative capabilities. Furthermore, to illustrate the underlying mechanism, the specific biological targets of EA were predicted and confirmed. Finally, EA-sEVs were encapsulated in GelMA hydrogel for investigating the pro-healing effects on diabetic wounds. EA was harmless to cell viability, increasing the possibility and safety of drug development. EA-engineered sEVs were fabricated by loading EA in sEVs. In vitro, EA-sEVs promoted the proliferation, migration, and transdifferentiation of HG-HDFs and the proliferation and migration of HG-HEKs. Mechanism analysis elucidated that epidermal growth factor receptor (EGFR) was the specific biological target of EA. EA interacting with EGFR was responsible for the functional improvement of HG-HDFs and HG-HEKs. In vivo, EA-sEVs encapsulated in GelMA promoted the healing of diabetic wounds by improving re-epithelialisation, collagen formation and the expression of EGFR. Gel-EA-sEVs promoted diabetic wound healing by improving biological functions of HDFs and HEKs. EGFR was first identified as the specific biological target of EA and was responsible for the functional improvement of HG-HDFs and HG-HEKs by Gel-EA-sEVs. Hence, Gel-EA-sEVs can serve as a new promising active dressing for diabetic wound treatment.

Spinal cord injury (SCI) is a severe disorder characterized by regeneration challenges in the central nervous system (CNS), resulting in permanent paralysis, loss of sensation, and abnormal autonomic functions. The complex pathophysiology of SCI poses challenges to traditional treatments, highlighting the urgent need for novel treatment approaches. Exosomes have emerged as promising candidates for SCI therapy because of their ability to deliver a wide range of bioactive molecules, such as RNAs, proteins, and lipids, to target cells with minimal immunogenicity, which contribute to anti-inflammatory, anti-apoptotic, autophagic, angiogenic, neurogenic, and axon remodeling activities. In this study, we classified exosomes from different sources into four categories based on the characteristics of the donor cells (mesenchymal stem cells, neurogenic cells, immune cells, vascular-associated cells) and provided a detailed summary and discussion of the current research progress and future directions for each source. We also conducted an in-depth investigation into the applications of engineered exosomes in SCI therapy, focusing on their roles in drug delivery and combination with surface engineering technologies and tissue engineering strategies. Finally, the challenges and prospects of exosomal clinical applications in SCI repair are described.

The regeneration and repair of natural bone is a complex and multifaceted process. Potentially, multifunctional scaffolds that exhibit synergistic effects of various biological activities and align with the dynamic bone healing process, are highly expected to achieve desirable bone repairing outcomes. Bioavailable magnesium (Mg) is an essential element taking part in bone regeneration via promoting angiogenesis and osteogenesis. Polyphenol gallic acid (GA) is an anti-inflammatory molecule that can modulate immune microenvironment. To control their release behaviors, Mg2+ and GA can react with each other to form metal-organic frameworks (MOF), which are then embedded into conductive porous scaffolds made of gelatin cryogel and poly(3,4-ethyldioxyethiophene): polystyrene sulfonate (PEDOT:PSS). In in vitro cell culture, the MOF-integrated conductive scaffold can simultaneously provide sustained supply of Mg2+ and GA to modulate the biological responses of a variety of cells. In in vivo evaluations, it shows remarkably enhanced new bone formation, as compared to groups of only MOF-contained non-conductive scaffold or conductive scaffold without MOF in rat calvarial defect model. In summary, conductive scaffold associated with sustained release of bioactive factors can serve as an effective treatment for inducing neo-bone growth benefiting from the synergistical contributions of diverse bioactive factors.

Utilizing drug-loaded hydrogels to restore nerve conductivity emerges as a promising strategy in the treatment of spinal cord injury (SCI). However, many of these hydrogels fail to deliver drugs on demand according to the dynamic SCI pathological features, resulting in poor functional recovery. Inspired by the post-SCI microenvironments, here we report a time-sequential and controllable drug delivery strategy using an injectable hydrogel responsive to reactive oxygen species (ROS) and matrix metalloproteinases (MMPs). This strategy includes two steps: first, the hydrogel responds to ROS and releases nanodrugs to scavenge ROS, thereby mitigating inflammation and protecting neurons from oxidative stress in the initial SCI stages; second, the accumulation of MMPs triggers the release of vascular endothelial growth factor from nanodrugs to promote angiogenesis and neural stem cell differentiation in the late stage of SCI. In two clinically relevant SCI models, a single injection of the hydrogel led to an efficient structural and functional recovery of SCI 6 weeks after the intervention. We observed less inflammation, fibrosis, and cavities but more angiogenesis and neurons in the hydrogel-treated injured spinal cord region compared with the untreated animals. The hydrogel exhibits mechanical strength and conductivity comparable to natural spinal cord, facilitating its further clinical translation.

Extracellular vesicles (EVs) have been actively explored for therapeutic applications in the context of cancer and other diseases. However, the poor tissue retention of EVs has limited the development of EV-based therapies. Here we report a facile approach to fabricating injectable EV hydrogels with tunable viscoelasticity and gelation temperature, by metabolically tagging EVs with azido groups and further crosslinking them with dibenzocyclooctyne-bearing polyethylene glycol via efficient click chemistry. One such EV gel has a gelation temperature of 39.4 °C, enabling in situ gelation of solution-form EVs upon injection into the body. The in situ formed gels are stable for over 4 weeks and can attract immune cells including dendritic cells over time in vivo. We further show that tumor EV hydrogels, upon subcutaneous injection, can serve as a long-term depot for EV-encased tumor antigens, providing an extended time for the modulation of dendritic cells and subsequent priming of tumor-specific CD8+ T cells. The tumor EV hydrogel also shows synergy with anti-PD-1 checkpoint blockade for tumor treatment, and is able to reprogram the tumor microenvironment. As a proof-of-concept, we also demonstrate that EV hydrogels can induce enhanced antibody responses than solution-form EVs over an extended time. Our study yields a facile and universal approach to fabricating injectable EV hydrogels with tunable mechanics and improving the therapeutic efficacy of EV-based therapies.

In the context of nasopharyngeal carcinoma (NPC) treatment, radiotherapy combined with immunotherapy (IR + RT) is gaining traction. This study focuses on analyzing exosomal proteins, particularly Phosphatase and Tensin Homolog (PTEN), for predicting the efficacy of NPC treatments. Serum samples from NPC patients and IR + RT recipients were utilized for exosome (Exo) extraction and subsequent transcriptomic and proteomic analyses to identify treatment-related proteins. Flow cytometry of cells and exosomal analysis were performed to examine these proteins. In vitro experiments using C666-1 cells and their Exos explored various cellular responses, while a murine subcutaneous NPC model investigated the impact of PTEN modulation on tumor growth and the immune microenvironment.

The study demonstrated that PTEN serves as a crucial predictive biomarker, with its expression changes correlated with M2 macrophage polarization and CD8+ T cell activity. This highlights the potential significance of PTEN in predicting treatment outcomes and influencing the immune response in NPC.

The findings suggest that PTEN could play a key role in enhancing the efficacy of NPC radiotherapy and immunotherapy. By shedding light on PTEN's impact on tumor growth and the immune microenvironment, this study lays the groundwork for future personalized therapeutic strategies in NPC treatment.

Rotator cuff tear (RCT) is a common musculoskeletal disease that poses challenges for functional regeneration of the tendon-bone interface (TBI). The transition of TBI between soft and hard tissues determines its structural and physiological environment complexity. Here, we present an injectable biopiezoelectric material PVA/CNF/BTO@PDA (Piezoelectric) hydrogel based on three-dimensional (3D) printing inspired by the "muscle-electrical coupling". This Piezoelectric hydrogel indicated desirable piezoelectric and mechanical properties, excellent biodegradability, and biosafety. In vitro, electrical stimulation from Piezoelectric hydrogel by the Flexcell Tissue Train system promoted the polarization of macrophages to the M2 phenotype, directing the targeted aggregation and zonal-specific differentiation of bone mesenchymal stem cells (BMSCs) for TBI formation. Also, optimal piezoelectric stimulation of the Piezoelectric hydrogel could alleviate inflammatory factor expression and regulate the osteotendinogenic differentiation of BMSCs under an H2O2/IL-1β inflammation environment. Furthermore, in vivo application of injectable Piezoelectric hydrogel demonstrates its regenerative potential, indicating that physiological repair with Piezoelectric hydrogel significantly accelerates and promotes TBI healing in a chronic RCT model. Therefore, our findings propose a new therapeutic strategy for functional TBI regeneration and enhance the treatment outcomes for RCT.

Neuronal damage of the retina is a leading cause of visual impairment in patients with retinal ischemia-reperfusion injury (RIRI). Building on our clinical and experimental findings, the substantial decrease in catalase activity correlates with increased hydrogen peroxide (H2O2)-mediated oxidative stress that is primarily localized to the outer nuclear layer (ONL) situated in the posterior segment of the retina. Accordingly, we design a neural stem cell exosome with polylysine (K10) decoration and catalase expression, named CataKNexo, which reaches the ONL and exerts synergistic antioxidant and neuroprotective therapy. Utilizing an in vitro retinal model recapitulating the layered architecture of the retina, we confirm that CataKNexo reaches the ONL through K10-mediated transcytosis. In RIRI model mice, CataKNexo prevents the retina from H2O2-induced cell death, exerts neuroprotection, and restores vision function to near-normal levels. Moreover, CataKNexo shows promising antioxidative, neuroprotective, and safety profiles in RIRI model Bama miniature pigs, highlighting its potential for clinical translation.

Traumatic brain injury (TBI) is a heterogeneous disease characterized by brain damage and functional impairment caused by external forces. Under the influence of multiple mechanisms, TBI can cause synaptic dysfunction, protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammatory cascade reactions, resulting in a high disability and mortality rate for patients and a heavy burden on families and society. Exosomes are cell-derived vesicles that encapsulate a variety of molecules, including proteins, lipids, mRNAs, and other small biomolecules. Among these, exosomes derived from mesenchymal stem cells (MSCs) have garnered significant attention owing to their therapeutic potential in the nervous system, offering broad clinical applicability. Recent studies have demonstrated that MSC-derived exosome injections in traumatic brain injury models effectively mitigate local inflammatory damage and promote nerve regeneration following injury. Owing to their small size, challenging replication, ease of preservation, and low immunogenicity, MSC exosomes are emerging as a promising therapeutic strategy for traumatic brain injury. This review explores the pathogenesis of traumatic brain injury, the underlying mechanisms of MSC exosome action, and the potential clinical applications of MSC exosomes in the treatment of traumatic brain injury.

Spinal cord injury (SCI) casts devastating and long-lasting impacts on the well-being of patients. Cognitive deficits and emotional disorders are common in individuals with SCI, yet the underlying mechanisms are not completely understood. Astrogliosis and glial scar formation occur during the subacute phase post-injury, playing complicated roles in remyelination and neurite regrowth. Therefore, we constructed a GFAP-IRES-Venus-AkaLuc knock-in mouse model for the corresponding studies. Surprisingly, complete spinal cord transection (SCT) surgery led to earlier and more prominent augmentation of bioluminescence in the brain than in the spinal cord. Bulk RNA sequencing revealed the activation of apoptotic signaling and the upregulation of serum and glucocorticoid-regulated kinase 1 (SGK1). The pattern of GFAP signals changed throughout the brain after SCT, as indicated by tissue clearing and immunostaining. Specifically, GFAP signals were intensified in the frontal association cortex (FrA), an encephalic region involved in associative learning and recognition memory processes. Further exploration unraveled that intensified GFAP signals in the FrA were attributed to apoptotic neurons with SGK1 upregulation, which was induced by sustained high glucocorticoid levels after SCT. The introduction of SGK1 silencing vectors confirmed that SGK upregulation in these FrA neurons exerted anti-apoptotic effects through NRF2/HO-1 signaling. In addition, SGK1 knockdown in FrA neurons aggravated the post-SCI depressive-like behaviors. Thus, ectopic SGK1 expression designated for limbic neurons could serve as a promising therapeutic target for the future development of treatments for spinal cord injuries.

Complete spinal cord injury (SCI) causes permanent locomotor, sensory and neurological dysfunctions. Targeting complex immunopathological microenvironment at SCI sites comprising inflammatory cytokines infiltration, oxidative stress and massive neuronal apoptosis, the conductive oriented nanofiber felt with efficient ROS clearance, anti-inflammatory effect and accelerating neural regeneration is constructed by step-growth addition polymerization and electrostatic spinning technique for SCI repair. The formation of innovative Fe3+-PDA-PAT chelate in nanofiber felt enhances hydrophilic, antioxidant, antibacterial, hemostatic and binding factor capacities, thereby regulating immune microenvironment of SCI. With the capabilities of up-regulating COX5A and STAT6 expressions, down-regulating the expressions of IL1β, CD36, p-ERK, NFκB2 and NFκB signaling pathway proteins, the nanofiber felt attenuates oxidative stress injury, promotes M2 macrophage polarization and down-regulates inflammatory response. After implantation into complete transection SCI rats, the nanofiber felt is revealed to recruit endogenous NSCs, induce the differentiation of NSCs into neurons while inhibit astrocytes formation and inflammation, reduces glia scar, and promotes angiogenesis, remyelination and neurological functional recovery. Overall, this innovative strategy provides a facile immune regulatory system to inhibit inflammatory response and accelerate nerve regeneration after SCI, and its targeted proteins and mechanisms are first elucidated, which holds great application promise in clinical treatment of complete SCI.

Common critical size bone defects encountered in clinical practice often result in inadequate bone regeneration,primarily due to the extent of damage surpassing the inherent capacity of the body for self-healing. Bone tissue engineering scaffolds possess the desirable characteristics of biomimetic bone structure, simulated extracellular matrix, optimal mechanical strength, and biological functionality, rendering them the preferred option for the treatment of bone defects. Chitosan demonstrates favorable biocompatibility, plasticity, and a range of biological activities, rendering it a highly appealing material. Chitosan and its derivatives have been found to exert an impact on bone repair through their ability to modulate macrophage polarization, angiogenesis, and the delicate equilibrium of bone remodeling. However, the efficacy of pure chitosan is constrained, necessitating its combination with other bioactive substances to achieve an optimal biomimetic scaffold that is compatible with the specific bone defect site. Chitosan is commonly utilized in the field of bone repair in four different application forms: rigid scaffold, hydrogel, membranes, and microspheres. In order to enhance comprehension of the benefits and constraints associated with chitosan, this review provides a comprehensive overview of the structure and biological properties of chitosan, the molecular mechanisms by which chitosan promotes osteogenic differentiation, the diverse methods of chitosan preparation for various applications, and the impacts of chitosan when loaded with bioactive substances.

Spinal cord injury (SCI) presents a formidable challenge in clinical settings, resulting in sensory and motor function loss and imposing significant personal and societal burdens. However, owning to the adverse microenvironment and limited regenerative capacity, achieving complete functional recovery after SCI remains elusive. Additionally, traditional interventions including surgery and medication have a series of limitations that restrict the effectiveness of treatment. Recently, tissue engineering (TE) has emerged as a promising approach for promoting neural regeneration and functional recovery in SCI, which can effectively delivery drugs into injury site and delivery cells and improve the survival and differential. Here, we outline the main pathophysiology events of SCI and the adverse microenvironment post injury, further discuss the materials and common assembly strategies used for scaffolds in SCI treatment, expound on the latest advancements in treatment methods based on materials and scaffolds for drug and cell delivery in detail, and propose future directions for SCI repair with TE and highlight potential clinical applications.

Electrically conductive hydrogels are highly hydrated 3D networks consisting of a hydrophilic polymer skeleton and electrically conductive materials. Conductive hydrogels have excellent mechanical and electrical properties and have further extensive application prospects in biomedical treatment and other fields. Whereas numerous electrically conductive hydrogels have been fabricated, a set of general principles, that can rationally guide the synthesis of conductive hydrogels using different substances and fabrication methods for various application scenarios, remain a central demand of electrically conductive hydrogels. This paper systematically summarizes the processing, performances, and applications of conductive hydrogels, and discusses the challenges and opportunities in this field. In view of the shortcomings of conductive hydrogels in high electrical conductivity, matchable mechanical properties, as well as integrated devices and machines, it is proposed to synergistically design and process conductive hydrogels with applications in complex surroundings. It is believed that this will present a fresh perspective for the research and development of conductive hydrogels, and further expand the application of conductive hydrogels.

Degenerative joint disease, known as osteoarthritis (OA), is characterized by pain, swelling, and decreased mobility. The illness has a major negative influence on patients' quality of life and is common around the world, especially among older people. Nevertheless, there are insufficient possibilities for early diagnosis and therapy. Extracellular vesicles, or EVs, control the immune response, tissue healing, and cellular communication.

This work offers a bibliometric representation of the areas of focus and correlations between extracellular vesicles and osteoarthritis. We searched for osteoarthritis and extracellular vesicles in publications in the Web of Science Core Collection (WoSCC) database. Bibliometrics, an R package, CiteSpace 6.1. R2, and VOSviewer 1.6.17 were used to perform bibliometric analyses of concentration fields, trends, and relevant factors.

944 papers from 59 nations were published; the countries that contributed the most to the field were China, the USA, and Italy. Professors Laura and Enrico are the top contributors. Sichuan University, Istituto Ortopedico Galeazzi, and Shanghai Jiao Tong University are the top three universities. The International Journal of Molecular Sciences is an excellent publication. Exosome, expression, knee osteoarthritis, extracellular vesicle, mesenchymal stem cell, osteoarthritis, and inflammation are the most often occurring keywords.

These results suggest areas of interest and focus for future research on EVs and OA. This trend suggests that the volume of literature on OA and EVs will continue to rise, with more research being published in the future. This study helps scholars understand current research hotspots in the field and may inspire future research.

Mesenchymal stem-cell-derived extracellular vesicles (MSC-EVs) are nanoscale lipid bilayer vesicles secreted by mesenchymal stem cells. They inherit the parent cell's attributes, facilitating tissue repair and regeneration, promoting angiogenesis, and modulating the immune response, while offering advantages like reduced immunogenicity, straightforward administration, and enhanced stability for long-term storage. These characteristics elevate MSC-EVs as highly promising in cell-free therapy with notable clinical potential. It is critical to delve into their pharmacokinetics and thoroughly elucidate their intracellular and in vivo trajectories. A detailed summary and evaluation of existing tracing strategies are needed to establish standardized protocols. Here, we have summarized and anticipated the research progress of MSC-EVs in various biomedical imaging techniques, including fluorescence imaging, bioluminescence imaging, nuclear imaging (PET, SPECT), tomographic imaging (CT, MRI), and photoacoustic imaging. The challenges and prospects of MSC-EV tracing strategies, with particular emphasis on clinical translation, have been analyzed, with promising solutions proposed.

Developing biomaterials capable of promoting bone regeneration in bacteria-infected sites is of utmost urgency for periodontal disease therapies. Here we produce a hybrid hydrogel by integrating CuS nanoparticles (CuSNPs), which could kill bacteria through photothermal therapy (PTT) triggered by a near infrared (NIR) light, and a gelatin methacryloyl (GelMA) hydrogel, which is injectable and biocompatible. Specifically, CuSNPs were precipitated by chitosan (CS) firstly, then grafted with methacrylic anhydride (MA) to form CuSNP@CS-MA, which was photo-crosslinked with GelMA to synthesize hybrid hydrogels (GelMA/CuSNP). The hybrid hydrogels exhibited a broad-spectrum antibacterial property that could be spatiotemprorally manipulated through applying a NIR light. Their mechanical properties were adjustable by controlling the concentration of CuSNPs, enabling the hydrogels to become more adapted to the oral diseases. Meanwhile, the hybrid hydrogels showed good cytocompatibility in vitro and improved hemostasis in vivo. Moreover, they accelerated alveolar osteogenesis and vascular genesis, successfully treating periodontis in four weeks in a rat model. GelMA/CuSNP hydrogels showed a broad-spectrum sterilization ability via PTT in vitro and outstanding antibacterial property in vivo, suggesting that the hybrid hydrogels could function in the challenging, bacteria-rich, oral environment. Such injectable hybrid hydrogels, capable of achieving both facilitated osteogenesis and NIR-inducible sterilization, represent a new biomaterial for treating periodontitis.

Exosomes are double-membrane vesicular nanoparticles in the category of extracellular vesicles, ranging in size from 30 to 150 nm, and are released from cells through a specific multi-step exocytosis process. Exosomes have emerged as promising tools for tissue repair due to their ability to transfer bioactive molecules that promote cell proliferation, differentiation, and tissue regeneration. However, the therapeutic application of exosomes is hindered by their rapid clearance from the body and limited retention at the injury site. To overcome these challenges, hydrogels, known for their high biocompatibility and porous structure, have been explored as carriers for exosomes. Hydrogels can provide a controlled release mechanism, prolonging the retention time of exosomes at targeted tissues, thus enhancing their therapeutic efficacy. This review focuses on the combination of different exosomes with hydrogels in the context of tissue repair. We first introduce the sources and functions of exosomes, particularly those from mesenchymal stem cells, and their roles in regenerative medicine. We then examine various types of hydrogels, highlighting their ability to load and release exosomes. Several strategies for encapsulating exosomes in hydrogels are discussed, including the impact of hydrogel composition and structure on exosome delivery efficiency. Finally, we review the applications of exosomes-loaded hydrogels in the repair of different tissues, such as skin, bone, cartilage, and nerve, and explore the challenges and future directions in this field. The combination of exosomes with hydrogels offers significant promise for advancing tissue repair strategies and regenerative therapies.

Protein self-assembly allows for the formation of diverse supramolecular materials from relatively simple building blocks. In this study, a single-component self-assembling hydrogel is developed using the recombinant protein CsgA, and its successful application for spinal cord injury repair is demonstrated. Gelation is achieved by the physical entanglement of CsgA nanofibrils, resulting in a self-supporting hydrogel at low concentrations (≥5 mg mL-1). By leveraging the programmability of the CsgA gene sequence, the bioactive hydrogel is enhanced by fusing functional peptide GHK. GHK is recognized for its anti-inflammatory, antioxidant, and neurotrophic factor-stimulating properties, making it a valuable addition to the hydrogel for spinal cord injury repair applications. In vitro experiments demonstrate that the CsgA-GHK hydrogel can modulate microglial M2 polarization, promote neuronal differentiation of neural stem cells, and inhibit astrocyte differentiation. Additionally, the hydrogel shows efficacy in alleviating inflammation and promotes neuronal regeneration at the injury site, leading to significant functional recovery in a rat model with compression injury spinal cord cavity. These findings lay the groundwork for developing a modular design platform for recombinant CsgA protein hydrogels in tissue repair applications.

Messenger RNA (mRNA)-based immunotherapies and protein in situ production therapies hold great promise for addressing theoretically all the diseases characterized by aberrant protein levels. The safe, stable, and precise delivery of mRNA to target cells via appropriate pharmaceutical strategies is a prerequisite for its optimal efficacy. In this review, we summarize the structural characteristics, mode of action, development prospects, and limitations of existing mRNA delivery systems from a pharmaceutical perspective, with an emphasis on the impacts from formulation adjustments and preparation techniques of non-viral vectors on mRNA stability, target site accumulation and transfection efficiency. In addition, we introduce strategies for synergistical combination of mRNA and small molecules to augment the potency or mitigate the adverse effects of mRNA therapeutics. Lastly, we delve into the challenges impeding the development of mRNA drugs while exploring promising avenues for future advancements.

After spinal cord injury (SCI), microglia polarization plays an important role in spinal cord recovery and axon regeneration. In this study, we conducted mRNA microarrays to identify genes associated with different microglial phenotypes. The results showed a correlation between microglial polarization and the PI3K/AKT signaling pathway, a key regulator of inflammatory responses. In addition, we found that Pectolinarin (PTR) could effectively inhibit lipopolysaccharide (LPS)-induced M1 polarization of microglia and facilitate their transition to the M2 phenotype by directly suppressing the PI3K/AKT signaling pathway. In our established animal model of SCI, it was confirmed that PTR treatment induced microglial polarization towards the M2 phenotype, resulting in reduced fibrous scar formation, enhanced myelin reconstitution, and improved axonal regeneration. In conclusion, targeting the PI3K/AKT signaling pathway with PTR presents a promising new direction for SCI treatment.

Deer antler blastema progenitor cells (ABPCs) are promising for regenerative medicine due to their role in annual antler regeneration, the only case of complete organ regeneration in mammals. ABPC-derived signals show great potential for promoting regeneration in tissues with limited natural regenerative ability. Our findings demonstrate the capability of extracellular vesicles from ABPCs (EVsABPC) to repair spinal cord injury (SCI), a condition with low regenerative capacity. EVsABPC significantly enhanced the proliferation of neural stem cells (NSCs) and activated neuronal regenerative potential, resulting in a 5.2-fold increase in axonal length. Additionally, EVsABPC exhibited immunomodulatory effects, shifting macrophages from M1 to M2. Engineered with activated cell-penetrating peptides (ACPPs), EVsABPC significantly outperformed EVs from rat bone marrow stem cells (EVsBMSC) and neural stem cells (EVsNSC), promoting a 1.3-fold increase in axonal growth, a 30.6% reduction in neuronal apoptosis, and a 2.6-fold improvement in motor function recovery. These findings support ABPC-derived EVs as a promising therapeutic candidate for SCI repair.

Exercise rehabilitation therapy has garnered widespread recognition for its beneficial effects on the restoration of locomotor function in individuals with spinal cord injury (SCI). Notably, resistance exercise has demonstrated significant improvements in muscle strength, coordination, and overall functional recovery. However, to optimize clinical management and mimic exercise-like effects, it is imperative to obtain a comprehensive understanding of the molecular alterations that underlie these positive effects.

We conducted a randomized controlled clinical trial investigating the effects of resistance exercise therapy for incomplete SCI. We integrated the analysis of plasma proteomics and peripheral blood mononuclear cells (PBMC) transcriptomics to explore the molecular and cellular changes induced by resistance exercise. Subsequently, we established a weight-loaded ladder-climbing mouse model to mimic the physiological effects of resistance exercise, and we analyzed the plasma proteome and metabolome, as well as the transcriptomes of PBMC and muscle tissue. Lastly, to confirm the transmissibility of the neuroprotective effects induced by resistance exercise, we intravenously injected plasma obtained from exercised male mice into SCI female mice during the non-acute phase.

Plasma proteomic and PBMC transcriptomic profiling underscored the notable involvement of the complement pathways and humoral immune response in the process of restoring locomotor function following SCI in the human trial. Moreover, it was emphasized that resistance exercise interventions could effectively modulate these pathways. Through employing plasma proteomic profiling and transcriptomic profiling of PBMC and muscle tissues in mice, our study revealed immunomodulatory responses that parallel those observed in human trials. In addition, our analysis of plasma metabolomics revealed an enhancement in lipid metabolism following resistance exercise. We observed that resistance exercise plasma exhibited significant effects in ameliorating locomotor disability after SCI via reducing demyelination and inhibiting neuronal apoptosis.

Our investigation elucidates the molecular alterations associated with resistance exercise therapy promoting recovery of locomotor function following incomplete SCI. Moreover, we demonstrate the direct neuroprotective effects delivered via exercise plasma injection, which facilitates spinal cord repair. Mechanistically, the comprehensive multi-omics analysis involving both human and mice reveals that the principal constituents responsible for the observed neuroprotective effects within the plasma are predominantly immunoregulatory factors, warranting further experimental validation.

The study was retrospectively registered on 17 July, 2024, in Chinese Clinical Trial Registry (No.: ChiCTR2400087038) at https://www.chictr.org.cn/ .

Exogenous neural stem cells (NSCs) have great potential to reconstitute damage spinal neural circuitry. However, regulating the metabolic reprogramming of NSCs for reliable nerve regeneration has been challenging. This report discusses the biomimetic dextral hydrogel (DH) with right-handed nanofibers that specifically reprograms the lipid metabolism of NSCs, promoting their neural differentiation and rapid regeneration of damaged axons. The underlying mechanism is the intrinsic stereoselectivity between DH and fatty acid-binding protein 5 (FABP5), which facilitates the transportation of fatty acids bound to FABP5 into the mitochondria and endoplasmic reticulum, subsequently augmenting fatty acid oxidation (FAO) levels and enriching sphingosine biosynthesis. In the rat SCI model, DH significantly improved the Basso-Beattie-Bresnahan (BBB) locomotor scores (over 3-fold) and the hindlimbs' compound muscle action potential (over 4-fold) compared with the untreated group, conveying a significant return of functional recovery. This finding of nanoscale chirality-dependent NSCs metabolic reprogramming provides insights into understanding stem cell physiology and presents opportunities for regenerative medicine.

Traumatic brain injury (TBI) often leads to enduring axonal damage and persistent neurological deficits. While PTEN's role in neuronal growth is recognized, its long-term activation changes post-TBI and its effects on sensory-motor circuits are not well understood. Here, it is demonstrated that the neuronal knockout of PTEN (PTEN-nKO) significantly enhances both structural and functional recovery over the long term after TBI. Importantly, in vivo, DTI-MRI revealed that PTEN-nKO promotes white matter repair post-TBI. Additionally, calcium imaging and electromyographic recordings indicated that PTEN-nKO facilitates cortical remapping and restores sensory-motor pathways. Mechanistically, PTEN negatively regulates the Akt/mTOR pathway by inhibiting Akt, thereby suppressing mTOR. Raptor is a key component of mTORC1 and its suppression impedes axonal regeneration. The restoration of white matter integrity and the improvements in neural function observed in PTEN-nKO TBI-treated mice are reversed by a PTEN/Raptor double knockout (PTEN/Raptor D-nKO), suggesting that mTORC1 acts as a key mediator. These findings highlight persistent alterations in the PTEN/Akt/mTORC1 axis are critical for neural circuit remodeling and cortical remapping post-TBI, offering new insights into TBI pathophysiology and potential therapeutic targets.

This study explores the potential of neuromodulation, specifically transcranial alternating current stimulation (tACS), as a promising rehabilitative therapy in spinal cord injury (SCI).

By meticulously optimizing treatment parameters and durations, our objective was to enhance nerve regeneration and facilitate functional recovery. To assess the efficacy of tACS, our experiments used the rat T10 SCI model. Motor function outcomes were measured using the Basso-Beattie-Bresnahan (BBB) scoring scale and footprint analysis. To thoroughly understand the impact of tACS, we conducted a series of histological evaluations two weeks post-injury. These included q-PCR, enzyme-linked immunosorbent assays (ELISA), transmission electron microscopy (TEM), immunofluorescence staining, and Western blotting. The mechanisms underlying the role of tACS will be elucidated through comprehensive analyses.

Simultaneously, tACS reduced the levels of reactive oxygen species (ROS), Fe, and malondialdehyde (MDH), and increased the levels of glutathione (GSH) after SCI. Additionally, tACS significantly enhanced motor function, reduced fibrotic scar tissue formation, and provided substantial neuroprotection. It also contributed to the restoration of the blood-spinal cord barrier and supported the regeneration of essential neural components, including axons, myelin, and synapses. The cGMP-PKG signalling pathway was identified as playing a crucial role in these processes.

Our findings suggest that tACS inhibits ferroptosis and necrotic degeneration by modulating the cGMP-PKG signalling pathway. This highlights the importance of tACS in promoting neural repair and functional recovery in SCI patients. Overall, tACS emerges as a highly effective and cost-efficient rehabilitative approach for SCI, offering new hope for improving patient outcomes.

Spinal cord injury (SCI) is a devastating condition without effective therapy currently available. The inflammatory cascade following SCI leads to neuronal apoptosis and glial cell activation. The utilization of local injectable hydrogels with immunotherapy drugs directly into injured nerve tissues represents a promising therapeutic strategy. Herein, injectable hydrogels grafted with clickable methylprednisolone (MP) and cellular adhesion peptide were developed using free radical polymerization for promoting nerve regeneration following SCI. MP conjugated hydrogels could modulate the immunoinflammatory microenvironment of SCI and sustain neuron survival. The multi-stiffness hydrogels were fabricated by adjusting concentration ratios to evaluate appropriate mechanical stimuli. In a model of dorsal root ganglion, MP grafted hydrogels with mechanical signals similar to those of adult rat spinal cords demonstrated superior efficacy in promoting dorsal root ganglion growth. MP grafted hydrogels could regulate the immune-inflammatory microenvironment, promote recovery of both motor function and sensory functions. The positive findings suggested that the interplay between immunomodulation and mechanical signals plays a crucial role in promoting nerve regeneration, indicating significant potential for hydrogels as a therapeutic approach for repairing SCI.

Regenerative medicine endeavors to restore damaged tissues and organs utilizing biological approaches. Utilizing biomaterials to target and regulate the pathophysiological processes of injured tissues stands as a crucial method in propelling this field forward. The Extracellular Vesicles-in-Hydrogel (EViH) system amalgamates the advantages of extracellular vesicles (EVs) and hydrogels, rendering it a prominent biomaterial in regenerative medicine with substantial potential for clinical translation. This review elucidates the development and benefits of the EViH system in tissue regeneration, emphasizing the interaction and impact of EVs and hydrogels. Furthermore, it succinctly outlines the pathophysiological characteristics of various types of tissue injuries such as wounds, bone and cartilage injuries, cardiovascular diseases, nerve injuries, as well as liver and kidney injuries, underscoring how EViH systems target these processes to address related tissue damage. Lastly, it explores the challenges and prospects in further advancing EViH-based tissue regeneration, aiming to impart a comprehensive understanding of EViH. The objective is to furnish a thorough overview of EViH in enhancing regenerative medicine applications and to inspire researchers to devise innovative tissue engineering materials for regenerative medicine.

Myocardial infarction (MI) remains one of the most common and lethal cardiovascular diseases (CVDs), leading to the deterioration of cardiac function due to myocardial cell necrosis and fibrous scar tissue formation. Myocardial infarction (MI) remains one of the most common and lethal cardiovascular diseases (CVDs), leading to the deterioration of cardiac function due to myocardial cell necrosis and fibrous scar tissue formation. After MI, the anisotropic structural properties of myocardial tissue are destroyed, and its mechanical and electrical microenvironment also undergoes a series of pathological changes, such as ventricular wall stiffness, abnormal contraction, conduction network disruption, and irregular electrical signal propagation, which may further induce myocardial remodeling and even lead to heart failure. Therefore, bionic reconstruction of the anisotropic structural-mechanical-electrical microenvironment of the infarct area is key to repairing damaged myocardium. This article first summarizes the pathological changes in muscle fibre structure and conductive microenvironment after cardiac injury, and focuses on the classification and preparation methods of anisotropic conductive materials. In addition, the effects of these anisotropic conductive materials on the behavior of cardiac resident cells after myocardial infarction, such as directional growth, maturation, proliferation and migration, and the differentiation fate of stem cells and the possible molecular mechanisms involved are summarized. The design strategies for anisotropic conductive scaffolds for myocardial repair in future clinical research are also discussed, with the aim of providing new insights for researchers in related fields.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising therapeutic strategy for spinal cord injury (SCI). These nanosized vesicles possess unique properties such as low immunogenicity and the ability to cross biological barriers, making them ideal carriers for delivering bioactive molecules to injured tissues. MSC-EVs have been demonstrated to exert multiple beneficial effects in SCI, including reducing inflammation, promoting neuroprotection, and enhancing axonal regeneration. Recent studies have delved into the molecular mechanisms underlying MSC-EV-mediated therapeutic effects. Exosomal microRNAs (miRNAs) have been identified as key regulators of various cellular processes involved in SCI pathogenesis and repair. These miRNAs can influence inflammation, oxidative stress, and apoptosis by modulating gene expression. This review summarized the current state of MSC-EV-based therapies for SCI, highlighting the underlying mechanisms and potential clinical applications. We discussed the challenges and limitations of translating these therapies into clinical practice, such as inconsistent EV production, complex cargo composition, and the need for targeted delivery strategies. Future research should focus on optimizing EV production and characterization, identifying key therapeutic miRNAs, and developing innovative delivery systems to maximize the therapeutic potential of MSC-EVs in SCI.

Accumulating research has shed light on the significance of skeletal interoception, in maintaining physiological and metabolic homeostasis related to bone health. This review provides a comprehensive analysis of how skeletal interoception influences bone homeostasis, delving into the complex interplay between the nervous system and skeletal system. One key focus of the review is the role of various factors such as prostaglandin E2 (PGE2) in skeletal health via skeletal interoception. It explores how nerves innervating the bone tissue communicate with the central nervous system to regulate bone remodeling, a process critical for maintaining bone strength and integrity. Additionally, the review highlights the advancements in biomaterials designed to utilize skeletal interoception for enhancing bone regeneration and treatment of bone disorders. These biomaterials, tailored to interact with the body's interoceptive pathways, are positioned at the forefront of innovative treatments for conditions like osteoporosis and fractures. They represent a convergence of bioengineering, neuroscience, and orthopedics, aiming to create more efficient and targeted therapies for bone-related disorders. In conclusion, the review underscores the importance of skeletal interoception in physiological regulation and its potential in developing more effective therapies for bone regeneration. It emphasizes the need for further research to fully understand the mechanisms of skeletal interoception and to harness its therapeutic potential fully.

Spinal cord injury (SCI) is a common nerve injury caused by external force, resulting in sensory and motor impairments. Previous studies demonstrated that inhibiting the neuroinflammation promoted SCI repair. However, these approaches are low efficient, and lack targeting specificity, and even require repeated and high doses of systemic administration. To address such issues, in the present study, chitosan-modified hydrogel microspheres encapsulating with zinc-doped bioactive glasses (CS-MG@Zn/BGs) is constructed for targeted repair of SCI. In vitro, the CS-MG@Zn/BGs effectively inhibited the acute inflammatory response initiated by microglia and promoted angiogenic activities. In vivo, CS-MG@Zn/BGs targeted the injured site, and attenuated neuroinflammation by inhibiting microglia infiltration and modulating microglia polarization toward M2 type. Furthermore, it facilitated vascular reconstruction, neuronal differentiation, axonal regeneration and remyelination at the injured site, and thereby promoted motor function recovery of SCI mice. The in vitro and in vivo results implied that CS-MG@Zn/BGs may be a promising alternative for the rehabilitation of SCI.

Stem-cell derived extracellular vesicles (EVs) have shown promise in preclinical spinal cord injury (SCI) models but lack a comprehensive literature review for clinical translation guidance.

This meta-analysis with trial sequential analysis systematically search PubMed, Web of Science, Embase, and Cochrane Library databases. Prespecified inclusion criteria were studies reporting on measurable outcomes relevant to SCI repair. Risk of bias and quality of reporting were assessed. Random-effects meta-analyses and subgroup analyses comparing natural and bio-engineered EVs were performed. The study was registered with PROSPERO (CRD42024512122).

The search identified 3935 records, of which 39 studies were included, totaling 1801 animals. Administration of EVs significantly improved locomotor function as measured by Basso-Beattie-Bresnahan or Basso-Mouse-Scale scores at 1 week (natural EVs: SMD 1.50, 95 % CI 1.06-1.95; bio-engineered EVs: SMD 1.93, 95 % CI 1.34-2.52) and 3 weeks (natural EVs: SMD 2.57, 95 % CI 1.96-3.17; bio-engineered EVs: SMD 3.16, 95 % CI 2.29-4.02) post-injury. Subgroup analyses indicated surface modification approaches were most effective among bio-engineered EV strategies. EVs also promoted nerve growth (SMD 2.95, 95 % CI 2.12-3.78), enhanced neuron conductivity (MD 0.75, 95 %CI 0.59-0.90), alleviated inflammation (SMD -3.12, 95 % CI -4.15--2.10), and reduced lesion size (SMD -2.90, 95 % CI -3.87--1.93).

Both natural and bio-engineered EVs improve functional and pathological outcomes in animal models of SCI. The enhanced benefits observed with bio-engineered EVs, particularly those utilizing surface modification approaches, highlight the importance of continued exploration into bio-engineering techniques to optimize EVs' therapeutic efficacy for SCI repair. Protocol Registration CRD42024512122.

Nanodrug delivery systems have revolutionized tumor therapy like never before. By overcoming the complexity of the tumor microenvironment (TME) and bypassing drug resistance mechanisms, nanotechnology has shown great potential to improve drug efficacy and reduce toxic side effects. This review examines the impact of the TME on drug resistance and recent advances in nanomedicine delivery systems to overcome this challenge. Characteristics of the TME such as hypoxia, acidity, and high interstitial pressure significantly reduce the effectiveness of chemotherapy and radiotherapy, leading to increased drug resistance in tumor cells. Then, this review summarizes innovative nanocarrier designs for these microenvironmental features, including hypoxia-sensitive nanoparticles, pH-responsive carriers, and multifunctional nanosystems that enable targeted drug release and improved drug penetration and accumulation in tumors. By combining nanotechnology with therapeutic strategies, this review offers a novel perspective by focusing on the innovative design of nanocarriers that interact with the TME, a dimension often overlooked in similar reviews. We highlight the dual role of these nanocarriers in therapeutic delivery and TME modulation, emphasize their potential to overcome drug resistance, and look at future research directions.