Drug delivery strategies for local immunomodulation hold tremendous promise compared to current clinical gold-standard systemic immunosuppression as they could improve the benefit to risk ratio of life-saving or life-enhancing transplants. Such strategies have facilitated prolonged graft survival in animal models at lower drug doses while minimizing off-target effects. Despite the promising outcomes in preclinical animal studies, progression of these strategies to clinical trials has faced challenges. A comprehensive understanding of the translational barriers is a critical first step towards clinical validation of effective immunomodulatory drug delivery protocols proven for safety and tolerability in pre-clinical animal models. This review overviews the current state-of-the-art in local immunomodulatory strategies for transplantation and outlines the key challenges hindering their clinical translation.

Microglia, as immune cells in the central nervous system, are closely related to cognitive impairment associated with type 2 diabetes (T2D). Preliminary explorations have investigated the relationship between T2D-related cognitive impairment and the activation and polarization of microglia. This review summarizes the potential mechanisms of microglial activation and polarization in the context of T2D. It discusses central inflammatory responses, neuronal apoptosis, amyloid-β deposition, and abnormal phosphorylation of Tau protein mediated by microglial activation and polarization, exploring the connections between microglial activation and polarization and T2D-related cognitive impairment from multiple perspectives. Additionally, this review provides references for future treatment targeting microglia in T2D-related cognitive impairment and for clinical translation.

Meniscus is vital for maintaining the anatomical and functional integrity of knee. Injuries to meniscus, commonly caused by trauma or degenerative processes, can result in knee joint dysfunction and secondary osteoarthritis, while current conservative and surgical interventions for meniscus injuries bear suboptimal outcomes. In the past decade, there has been a significant focus on advancing meniscus tissue engineering, encompassing isolated scaffold strategies, biological augmentation, physical stimulus, and meniscus organoids, to improve the prognosis of meniscus injuries. Despite noteworthy promising preclinical results, translational gaps and inconsistencies in the therapeutic efficiency between preclinical and clinical studies exist. This review comprehensively outlines the developments in meniscus tissue engineering over the past decade (Scheme 1). Reasons for the discordant results between preclinical and clinical trials, as well as potential strategies to expedite the translation of bench-to-bedside approaches are analyzed and discussed.

The gut microbiota, mainly resides in the colon, possesses a remarkable ability to metabolize different substrates to create bioactive substances, including short-chain fatty acids, indole-3-propionic acid, and secondary bile acids. In the liver, bile acids are synthesized from cholesterol and then undergo modification by the gut microbiota. Beyond those reclaimed by the enterohepatic circulation, small percentage of bile acids escaped reabsorption, entering the systemic circulation to bind to several receptors, such as farnesoid X receptor (FXR), thereby exert their biological effects. Gut microbiota interplays with bile acids by affecting their synthesis and determining the production of secondary bile acids. Reciprocally, bile acids shape out the structure of gut microbiota. The interplay of bile acids and FXR is involved in the development of multisystemic conditions, encompassing metabolic diseases, hepatobiliary diseases, immune associated disorders. In the review, we aim to provide a thorough review of the intricate crosstalk between the gut microbiota and bile acids, the physiological roles of bile acids and FXR in mammals\' health and disease, and the clinical translational considerations of gut microbiota-bile acids-FXR in the treatment of the diseases.

Mesenchymal stromal cell (MSC) apoptosis is required for in vivo immunosuppression. However, the induction of apoptosis is heavily dependent on the recipient\'s immune system. In graft-versus-host disease (GvHD), patients who fail to respond to MSCs are in fact those whose immune cells are unable to induce MSC apoptosis ex vivo. The information is critical to explain why responses in clinical trials vary even though the same sources of MSC products are infused. More importantly, it highlights the need for an alternative MSC treatment for the nonresponders. By using a mouse model of ovalbumin (OVA)-induced allergic inflammation, we demonstrated that we could generate apoptotic MSCs (ApoMSCs) in vitro and use them to successfully reduce allergic airway inflammation. In order to address the logistics of their potential future clinical application, we have shown that ApoMSCs could be cryopreserved without impairing efficacy compared to freshly generated ApoMSCs. We have also highlighted that MSCs need to undergo complete apoptosis before cryopreservation to retain their immunosuppressive activity. The cryopreserved ApoMSCs could serve as a potential future off-the-shelf cellular product, in particular for patients who suffer from inflammatory conditions yet do not harbor the immune capacity to induce MSC apoptosis in vivo. Our data provide proof-of-concept that under laboratory conditions, ApoMSCs can be successfully frozen and thawed without affecting their anti-inflammatory activity, as tested in a murine model of allergic inflammation.

Macrocyclic compounds have emerged as potent tools in the field of drug design, offering unique advantages for enhancing molecular recognition, improving pharmacokinetic properties, and expanding the chemical space accessible to medicinal chemists. This review delves into the evolutionary trajectory of macrocyclic-based strategies, tracing their journey from laboratory innovations to clinical applications. Beginning with an exploration of the defining structural features of macrocycles and their impact on drug-like characteristics, this discussion progresses to highlight key design principles that have facilitated the development of diverse macrocyclic drug candidates. Through a series of illustrative representative case studies from approved macrocyclic drugs and candidates spanning various therapeutic areas, particular emphasis is placed on their efficacy in targeting challenging protein-protein interactions, enzymes, and receptors. Additionally, this review thoroughly examines how macrocycles effectively address critical issues such as metabolic stability, oral bioavailability and selectivity. Valuable insights into optimization strategies employed during both approved and clinical phases underscore successful translation of promising leads into efficacious therapies while providing valuable perspectives on harnessing the full potential of macrocycles in drug discovery and development endeavors.

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia, leading to various vascular complications. Accumulating evidence indicates that endothelial colony-forming cells (ECFCs) have attractive prospects for repairing and restoring blood vessels. Thus, ECFCs may be a novel therapeutic option for diabetic patients with vascular complications who require revascularization therapy. However, it has been reported that the function of ECFCs is impaired in DM, which poses challenges for the autologous transplantation of ECFCs. In this review, we summarize the molecular mechanisms that may be responsible for ECFC dysfunction and discuss potential strategies for improving the therapeutic efficacy of ECFCs derived from patients with DM. Finally, we discuss barriers to the use of ECFCs in human studies in light of the fact that there are no published reports using these cells in humans.

Nerve injury can significantly impair motor, sensory, and autonomic functions. Understanding nerve degeneration, particularly Wallerian degeneration, and the mechanisms of nerve regeneration is crucial for developing effective treatments. This manuscript reviews the use of advanced hydrogels that have been researched to enhance nerve regeneration. Hydrogels, due to their biocompatibility, tunable properties, and ability to create a supportive microenvironment, are being explored for their effectiveness in nerve repair. Various types of hydrogels, such as chitosan-, alginate-, collagen-, hyaluronic acid-, and peptide-based hydrogels, are discussed for their roles in promoting axonal growth, functional recovery, and myelination. Advanced formulations incorporating growth factors, bioactive molecules, and stem cells show significant promise in overcoming the limitations of traditional therapies. Despite these advancements, challenges in achieving robust and reliable nerve regeneration remain, necessitating ongoing research to optimize hydrogel-based interventions for neural regeneration.

Stem cell-based therapies have emerged as a promising approach for treating various neurological disorders by harnessing the regenerative potential of stem cells to restore damaged neural tissue and circuitry. This comprehensive review provides an in-depth analysis of the current state of stem cell applications in primary neurological conditions, including Parkinson\'s disease (PD), Alzheimer\'s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other related disorders. The review begins with a detailed introduction to stem cell biology, discussing the types, sources, and mechanisms of action of stem cells in neurological therapies. It then critically examines the preclinical evidence from animal models and early human trials investigating the safety, feasibility, and efficacy of different stem cell types, such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs). While ESCs have been studied extensively in preclinical models, clinical trials have primarily focused on adult stem cells such as MSCs and NSCs, as well as iPSCs and their derivatives. We critically assess the current state of research for each cell type, highlighting their potential applications and limitations in different neurological conditions. The review synthesizes key findings from recent, high-quality studies for each neurological condition, discussing cell manufacturing, delivery methods, and therapeutic outcomes. While the potential of stem cells to replace lost neurons and directly reconstruct neural circuits is highlighted, the review emphasizes the critical role of paracrine and immunomodulatory mechanisms in mediating the therapeutic effects of stem cells in most neurological disorders. The article also explores the challenges and limitations associated with translating stem cell therapies into clinical practice, including issues related to cell sourcing, scalability, safety, and regulatory considerations. Furthermore, it discusses future directions and opportunities for advancing stem cell-based treatments, such as gene editing, biomaterials, personalized iPSC-derived therapies, and novel delivery strategies. The review concludes by emphasizing the transformative potential of stem cell therapies in revolutionizing the treatment of neurological disorders while acknowledging the need for rigorous clinical trials, standardized protocols, and multidisciplinary collaboration to realize their full therapeutic promise.

Biodegradable magnesium-based metal guided bone regeneration (GBR) membranes possess excellent mechanical properties, biodegradability, and osteopromotive capabilities, making them ideal implants for the treatment of maxillofacial bone defects. This review summarizes the current status and future research trends related to magnesium-based GBR membranes. First, the research history and application fields of magnesium-based metals are introduced, and the advantages of the use of magnesium-based materials for GBR membranes, including their mechanical properties, biocompatibility, osteopromotive performance, and underlying mechanisms are discussed. Finally, this review addresses the current limitations of magnesium-based GBR membranes and their applications and prospects in the field of dentistry. In conclusion, considerable advancements have been in fundamental and translational research on magnesium-based GBR membranes, which lays a crucial foundation for the treatment of maxillofacial bone defects.
可降解镁基金属引导骨再生（GBR）膜具有良好的机械性能、生物降解性和生物促成骨性能，是治疗颌面部骨缺损的理想植入物。本文对镁基金属引导骨再生膜的现状和未来的研究趋势进行阐述。首先介绍了镁基金属的研究历史及应用领域，随后从镁基金属GBR膜的机械性能、生物相容性和促成骨性能及其机制方面介绍了镁基金属制备GBR膜的应用优势，最后对当前镁基金属GBR膜的局限性及在口腔医学中的应用和展望进行介绍。镁基金属GBR膜在基础和转化研究方面都取得了重要的进展，为治疗口腔颌面部的骨缺损奠定了重要的基础。.