Self-adaptive pyroptosis-responsive nanoliposomes block pyroptosis in autoimmune inflammatory diseases.

Nanoliposomes have a broad range of applications in the treatment of autoimmune inflammatory diseases because of their ability to considerably enhance drug transport. For their clinical application, nanoliposomes must be able to realize on-demand release of drugs at disease sites to maximize drug-delivery efficacy and minimize side effects. Therefore, responsive drug-release strategies for inflammation treatment have been explored; however, no specific design has been realized for a responsive drug-delivery system based on pyroptosis-related inflammation. Herein, we report a pioneering strategy for self-adaptive pyroptosis-responsive liposomes (R8-cardiolipin-containing nanoliposomes encapsulating dimethyl fumarate, RC-NL@DMF) that precisely release encapsulated anti-pyroptotic drugs into pyroptotic cells. The activated key pyroptotic protein, the N-terminal domain of gasdermin E, selectively integrates with the cardiolipin of liposomes, thus forming pores for controlled drug release, pyroptosis, and inflammation inhibition. Therefore, RC-NL@DMF exhibited effective therapeutic efficacies to alleviate autoimmune inflammatory damages in zymosan-induced arthritis mice and dextran sulfate sodium-induced inflammatory bowel disease mice. Our novel approach holds great promise for self-adaptive pyroptosis-responsive on-demand drug delivery, suppressing pyroptosis and treating autoimmune inflammatory diseases.

Advances in Hydrogels for Meniscus Tissue Engineering: A Focus on Biomaterials, Crosslinking, Therapeutic Additives.

Meniscus tissue engineering (MTE) has emerged as a promising strategy for meniscus repair and regeneration. As versatile platforms, hydrogels have gained significant attention in this field, as they possess tunable properties that allow them to mimic native extracellular matrices and provide a suitable microenvironment. Additionally, hydrogels can be minimally invasively injected and can be adjusted to match the shape of the implant site. They can conveniently and effectively deliver bioactive additives and demonstrate good compatibility with other functional materials. These inherent qualities have made hydrogel a promising candidate for therapeutic approaches in meniscus repair and regeneration. This article provides a comprehensive review of the advancements made in the research on hydrogel application for meniscus tissue engineering. Firstly, the biomaterials and crosslinking strategies used in the formation of hydrogels are summarized and analyzed. Subsequently, the role of therapeutic additives, including cells, growth factors, and other active products, in facilitating meniscus repair and regeneration is thoroughly discussed. Furthermore, we summarize the key issues for designing hydrogels used in MTE. Finally, we conclude with the current challenges encountered by hydrogel applications and suggest potential solutions for addressing these challenges in the field of MTE. We hope this review provides a resource for researchers and practitioners interested in this field, thereby facilitating the exploration of new design possibilities.

Single-Cell Microgel Encapsulation Improves the Therapeutic Efficacy of Mesenchymal Stem Cells in Treating Intervertebral Disc Degeneration via Inhibiting Pyroptosis.

While mesenchymal stem cell (MSC) shows great potentials in treating intervertebral disc degeneration, most MSC die soon after intradiscal transplantation, resulting in inferior therapeutic efficacy. Currently, bulk hydrogels are the common solution to improve MSC survival in tissues, although hydrogel encapsulation impairs MSC migration and disrupts extracellular microenvironment. Cell hydrogel encapsulation has been proposed to overcome the limitation of traditional bulk hydrogels, yet this technique has not been used in treating disc degeneration. Using a layer-by-layer self-assembly technique, we fabricated alginate and gelatin microgel to encapsulate individual MSC for treating disc degeneration. The small size of microgel allowed intradiscal injection of coated MSC. We demonstrated that pyroptosis was involved in MSC death under oxidative stress stimulation, and microgel coating suppressed pyroptosis activation by maintaining mitochondria homeostasis. Microgel coating protected MSC in the harsh disc microenvironment, while retaining vital cellular functions such as migration, proliferation, and differentiation. In a rat model of disc degeneration, coated MSC exhibits prolonged retention in the disc and better efficacy of attenuating disc degeneration, as compared with bare MSC treatment alone. Further, microgel-coated MSC exhibited improved therapeutic effects in treating disc degeneration via suppressing the activation of pyroptosis in the disc. For the first time, microgel-encapsulated MSC was used to treat disc degeneration and obtain encouraging outcomes. The developed biocompatible single-cell hydrogel is an effective strategy to protect MSC and maintain cellular functions and may be an efficacious approach to improving the efficacy of MSC therapy in treating disc degeneration. The objective of this study is to improve the efficacy of cell therapy for treating disc degeneration using single-cell hydrogel encapsulation and further to understand related cytoprotective mechanisms.

Comparison of the ability of exosomes and ectosomes derived from adipose-derived stromal cells to promote cartilage regeneration in a rat osteochondral defect model.

BACKGROUND: Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) offer promising prospects for stimulating cartilage regeneration. The different formation mechanisms suggest that exosomes and ectosomes possess different biological functions. However, little attention has been paid to the differential effects of EV subsets on cartilage regeneration. METHODS: Our study compared the effects of the two EVs isolated from adipose-derived MSCs (ASCs) on chondrocytes and bone marrow-derived MSCs (BMSCs) in vitro. Additionally, we loaded the two EVs into type I collagen hydrogels to optimize their application for the treatment of osteochondral defects in vivo. RESULTS: In vitro experiments demonstrate that ASC-derived exosomes (ASC-Exos) significantly promoted the proliferation and migration of both cells more effectively than ASC-derived ectosomes (ASC-Ectos). Furthermore, ASC-Exos facilitated a stronger differentiation of BMSCs into chondrogenic cells than ASC-Ectos, but both inhibited chondrocyte apoptosis to a similar extent. In the osteochondral defect model of rats, ASC-Exos promoted cartilage regeneration in situ better than ASC-Ectos. At 8 weeks, the hydrogel containing exosomes group (Gel + Exo group) had higher macroscopic and histological scores, a higher value of trabecular bone volume fraction (BV/TV), a lower value of trabecular thickness (Tb.Sp), and a better remodeling of extracellular matrix than the hydrogel containing ectosomes group (Gel + Ecto group). At 4 and 8 weeks, the expression of CD206 and Arginase-1 in the Gel + Exo group was significantly higher than that in the Gel + Ecto group. CONCLUSION: Our findings indicate that administering ASC-Exos may be a more effective EV strategy for cartilage regeneration than the administration of ASC-Ectos.

An On-Demand Collaborative Innate-Adaptive Immune Response to Infection Treatment.

Deep tissue infection is a common clinical issue and therapeutic difficulty caused by the disruption of the host antibacterial immune function, resulting in treatment failure and infection relapse. Intracellular pathogens are refractory to elimination and can manipulate host cell biology even after appropriate treatment, resulting in a locoregional immunosuppressive state that leads to an inadequate response to conventional anti-infective therapies. Here, a novel antibacterial strategy involving autogenous immunity using a biomimetic nanoparticle (NP)-based regulating system is reported to induce in situ collaborative innate-adaptive immune responses. It is observed that a macrophage membrane coating facilitates NP enrichment at the infection site, followed by active NP accumulation in macrophages in a mannose-dependent manner. These NP-armed macrophages exhibit considerably improved innate capabilities, including more efficient intracellular ROS generation and pro-inflammatory factor secretion, M1 phenotype promotion, and effective eradication of invasive bacteria. Furthermore, the reprogrammed macrophages direct T cell activation at infectious sites, resulting in a robust adaptive antimicrobial immune response to ultimately achieve bacterial clearance and prevent infection relapse. Overall, these results provide a conceptual framework for a novel macrophage-based strategy for infection treatment via the regulation of autogenous immunity.

Comparative Effects of Exosomes and Ectosomes Isolated From Adipose-Derived Mesenchymal Stem Cells on Achilles Tendinopathy in a Rat Model.

BACKGROUND: Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have gained momentum as a treatment for tendinopathy. Multiple studies have demonstrated significant differences in cargo composition between the 2 subtypes of MSC-EVs (ie, exosomes and ectosomes), which may result in different therapeutic effects. However, the effects of the 2 EV subtypes on tendinopathy have not yet been compared. PURPOSE: To compare the effects of adipose stem cell-derived exosomes (ASC-Exos) and ectosomes (ASC-Ectos) on Achilles tendinopathy. STUDY DESIGN: Controlled laboratory study. METHODS: Rats were administered collagenase injections to generate a model of Achilles tendinopathy. A week later, 36 rats were randomly assigned to 3 groups. In each group, Achilles tendons were injected with equal volumes of ASC-Exos, ASC-Ectos, or saline (12 legs/group). The healing outcomes were evaluated by magnetic resonance imaging, histology, immunohistochemistry, transmission electron microscopy, and biomechanical testing at 3 and 5 weeks after collagenase injection. RESULTS: At 3 and 5 weeks, the ASC-Exo group had better histological scores (P = .0036 and P = .0276, respectively), a lower fibril density (P < .0001 and P = .0310, respectively), and a larger collagen diameter (P = .0052 and P < .0001, respectively) than the ASC-Ecto group. At 5 weeks, the expression of collagen type 1 and CD206 in the ASC-Exo group was significantly higher than that in the ASC-Ecto group (P = .0025 and P = .0010, respectively). Regarding biomechanical testing, the ASC-Exo group showed higher failure load (P = .0005), tensile stress (P < .0001), and elastic modulus (P < .0001) than the ASC-Ecto group. CONCLUSION: ASC-Exos had more beneficial effects on tendon repair than ASC-Ectos in a rat model of Achilles tendinopathy. CLINICAL RELEVANCE: Administration of ASC-EVs may have the potential to treat Achilles tendinopathy, and delivery of ASC-Exos could provide additional benefits. It is necessary to compare the healing responses caused by different EV subtypes to further understand their effects on tendinopathy and to aid clinical decision making.