Delivery Of Bioactive Molecules Research Articles

Micro-thin hydrogel coating integrated in 3D printing for spatiotemporal delivery of bioactive small molecules

Three-dimensional (3D) printing incorporated with controlled delivery is an effective tool for complex tissue regeneration. Here, we explored a new strategy for spatiotemporal delivery of bioactive cues by establishing a precise-controlled micro-thin coating of hydrogel carriers on 3D-printed scaffolds. We optimized the printing parameters for three hydrogel carriers, fibrin cross-linked with genipin, methacrylate hyaluronic acid, and multidomain peptides, resulting in homogenous micro-coating on desired locations in 3D printed polycaprolactone microfibers at each layer. Using the optimized multi-head printing technique, we successfully established spatial-controlled micro-thin coating of hydrogel layers containing profibrogenic small molecules (SMs), Oxotremorine M and PPBP maleate, and a chondrogenic cue, Kartogenin. The delivered SMs showed sustained releases up to 28 d and guided regional differentiation of mesenchymal stem cells, thus leading to fibrous and cartilaginous tissue matrix formation at designated scaffold regionsin vitroandin vivo. Our micro-coating of hydrogel carriers may serve as an efficient approach to achieve spatiotemporal delivery of various bioactive cues through 3D printed scaffolds for engineering complex tissues.

The Use of Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles in the Treatment of Osteoarthritis: Insights from Preclinical Studies.

Osteoarthritis (OA) is a prominent cause of disability, and has severe social and economic ramifications across the globe. The main driver of OA's pervasiveness is the fact that no current medical interventions exist to reverse or even attenuate the degeneration of cartilage within the articular joint. Crucial for cell-to-cell communication, extracellular vesicles (EVs) contribute to OA progression through the delivery of bioactive molecules in the inflammatory microenvironment. By repurposing this acellular means of signal transmission, therapeutic drugs may be administered to degenerated cartilage tissue in the hopes of encouraging regeneration. Positive outcomes are apparent in in vivo studies on this subject; however, for this therapy to prove itself in the clinical world, efforts towards standardizing the characterization, application, biological contents, and dosage are essential.

In Vitro Models for Peripheral Nerve Regeneration.

Peripheral nerve injury (PNI) resulting in lesions is highly prevalent clinically, but current therapeutic approaches fail to provide satisfactory outcomes in many patients. While peripheral nerves have intrinsic regenerative capacity, the regenerative capabilities of peripheral nerves are often insufficient to restore full functionality. This highlights an unmet need for developing more effective strategies to repair damaged peripheral nerves and improve regenerative success. Consequently, researchers are actively exploring a variety of therapeutic strategies, encompassing the local delivery of trophic factors or bioactive molecules, the design of advanced biomaterials that interact with regenerating axons, and augmentation with nerve guidance conduits or complex prostheses. However, clinical translation of these technologies remains limited, emphasizing the need for continued research on peripheral nerve regeneration modalities that can enhance functional restoration. Experimental models that accurately recapitulate key aspects of peripheral nerve injury and repair biology can accelerate therapeutic development by enabling systematic testing of new techniques. Advancing regenerative therapies for PNI requires bridging the gap between basic science discoveries and clinical application. This review discusses different in vitro models of peripheral nerve injury and repair, including their advantages, limitations, and potential applications.

Pterostilbene-loaded PLGA nanoparticles alter phenylpropanoid and oxylipin metabolism in Solanum lycopersicum L. leaves

Due to the fast-changing global climate, conventional agricultural systems have to deal with more unpredictable and harsh environmental conditions leading to compromise food production. The application of phytonanotechnology can ensure safer and more sustainable crop production, allowing the target-specific delivery of bioactive molecules with great and partially explored positive effects for agriculture, such as an increase in crop production and plant pathogen reduction. In this study, the effect of free pterostilbene (PTB) and poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) loaded with pterostilbene was investigated on Solanum lycopersicum L. metabolism. An untargeted NMR-based metabolomics approach was used to examine primary and secondary metabolism whereas a targeted HPLC–MS/MS-based approach was used to explore the impact on defense response subjected to anti-oxidant effect of PTB, such as free fatty acids, oxylipins and them impact on hormone biosynthesis, in particular salicylic and jasmonic acid. In tomato leaves after treatment with PTB and PLGA NPs loaded with PTB (NPs + PTB), both NPs + PTB and free PTB treatments increased GABA levels in tomato leaves. In addition, a decrease of quercetin-3-glucoside associated with the increase in caffeic acid was observed suggesting a shift in secondary metabolism towards the biosynthesis of phenylpropanoids and other phenolic compounds. An increase of behenic acid (C22:0) and a remodulation of oxylipin metabolism deriving from the linoleic acid (i.e. 9-HpODE, 13-HpODE and 9-oxo-ODE) and linolenic acid (9-HOTrE and 9-oxoOTrE) after treatment with PLGA NPs and PLGA NPs + PTB were also found as a part of mechanisms of plant redox modulation. To the best of our knowledge, this is the first study showing the role of PLGA nanoparticles loaded with pterostilbene in modulating leaf metabolome and physiology in terms of secondary metabolites, fatty acids, oxylipins and hormones. In perspective, PLGA NPs loaded with PTB could be used to reshape the metabolic profile to allow plant to react more quickly to stresses.

A Reconfigurable Proangiogenic Hydrogel Patch Enabling Minimally Invasive Drug Delivery.

Hydrogel is widely used for the sustained delivery of bioactive molecules that can treat various injuries, diseases, and tissue defects. However, inserting hydrogel implants without disrupting their functionality and microstructure often requires a large incision, leading to potential complications, such as infection, scarring, and pain. The gel implant is often manually rolled and inserted through a catheter for a minimally invasive delivery. However, success heavily depends on the user's skills, which can inadvertently damage the implant. To address this issue, we developed a reconfigurable hydrogel patch that can self-fold into a small tube and unfold spontaneously after implantation through a catheter. The hydrogel path was assembled by layering a drug-releasing poly(ethylene glycol) diacrylate (PEGDA) hydrogel sheet onto a PEGDA and polyethylenimine (PEI) hydrogel sheet, which rapidly swells and degrades homogeneously at controlled rates. The dynamics of the self-folding and unfolding process could be controlled by differences in the expansion ratio and elastic modulus between the two gel layers according to a mathematical model that closely matched experimental results. The unfolding process triggered a sustained release of the protein cargo. Specifically, the reconfigurable gel loaded with angiopoietin 1 significantly enhanced neovascularization, nearly doubling the vascular density compared to the control group following implantation through a tube with 15% smaller diameter than the original shape of the gel patch. This gel biopatch will be broadly useful for the minimally invasive delivery of a wide array of therapeutic molecules, potentially enhancing therapeutic outcomes.

Multi-crosslinked hydrogels composed of hyaluronic acid, silk fibroin and chitosan nanoparticles with capacity of bioactive molecule delivery and degradation tolerance for cartilage tissue engineering

Polymer hydrogels intended for cartilage repair applications need to be mechanically competent and degradation-endurable. Combining these essential properties jointly into the natural polymer hydrogels is an ongoing challenge. Here, a new type of multi-crosslinked composite hydrogel with enhanced mechanical and degradation-resistant properties has been developed using thiolated hyaluronic acid (THA), silk fibroin (SF), and thiolated chitosan (TCH) nanoparticles (NPs). In addition, kartogenin is loaded into TCH NPs, and meanwhile, platelet-derived growth factor-BB is incorporated into the gel matrix in combination with fucoidan for bestowing collaborative biofunctions upon the composite hydrogels. The optimally achieved THA/SF/TCH hydrogels exhibit strong, elastic, and tough characteristics and enhanced degradation tolerance. The THA/SF/TCH hydrogels also show a confirmative ability to stimulate the migration of bone marrow mesenchymal stem cells and induce their chondrogenic differentiation. These results suggest that these composite gels have promising potential as an injective material for endogenous articular cartilage repair and regeneration.

Local delivery of platelet-derived factors mitigates ischemia and preserves ovarian function through angiogenic modulation: A personalized regenerative strategy for fertility preservation

As the most prominent and ideal modality in female fertility preservation, ovarian tissue cryopreservation, and transplantation often confront the challenge of ischemic damage and follicular loss from avascular transplantation. To surmount this impediment, we engineered a novel platelet-derived factors-encapsulated fibrin hydrogel (PFH), a paradigmatic biomaterial. PFH encapsulates autologous platelet-derived factors, utilizing the physiological blood coagulation cascade for precise local delivery of bioactive molecules. In our study, PFH markedly bolstered the success of avascular ovarian tissue transplantation. Notably, the quantity and quality of follicles were preserved with improved neovascularization, accompanied by decreased DNA damage, increased ovulation, and superior embryonic development rates under a Low-concentration Platelet-rich plasma-derived factors encapsulated fibrin hydrogel (L-PFH) regimen. At a stabilized point of tissue engraftment, gene expression analysis mirrored normal ovarian tissue profiles, underscoring the effectiveness of L-PFH in mitigating the initial ischemic insult. This autologous blood-derived biomaterial, inspired by nature, capitalizes on the blood coagulation cascade, and combines biodegradability, biocompatibility, safety, and cost-effectiveness. The adjustable properties of this biomaterial, even in injectable form, extend its potential applications into the broader realm of personalized regenerative medicine. PFH emerges as a promising strategy to counter ischemic damage in tissue transplantation, signifying a broader therapeutic prospect. (197 words)

Bioactive Molecules Delivery through Ferritin Nanoparticles: Sum Up of Current Loading Methods.

Ferritin (Ft) is a protein with a peculiar three-dimensional architecture. It is characterized by a hollow cage structure and is responsible for iron storage and detoxification in almost all living organisms. It has attracted the interest of the scientific community thanks to its appealing features, such as its nano size, thermal and pH stability, ease of functionalization, and low cost for large-scale production. Together with high storage capacity, these properties qualify Ft as a promising nanocarrier for the development of delivery systems for numerous types of biologically active molecules. In this paper, we introduce the basic structural and functional aspects of the protein, and summarize the methods employed to load bioactive molecules within the ferritin nanocage.

Gelatin-nanocellulose stabilized emulsion-filled hydrogel beads loaded with curcumin: Preparation, encapsulation and release behavior

In this study, the curcumin was firstly encapsulated in gelatin (GLT) and/or cellulose nanocrystals (CNC) stabilized emulsions, then further mixed with sodium alginate (SA) to form emulsion-filled hydrogel beads loaded with curcumin (Cur). The Cur-loaded emulsions showed a droplet size of 20.3–24.4 μm with a uniform distribution. Introducing CNC and/or SA increased the viscosity of emulsions accompanied by viscoelastic transition, while the modulus was reduced due to destruction of GLT gel. Cur was doubly immobilized in the hydrogel beads with >90 % of encapsulation efficiency. The results of simulated gastrointestinal tract experiments revealed that the beads possessed a good pH sensitivity and controlled release behavior to prolong the retention of Cur in the gastrointestinal tract. After 6 h of UV irradiation, the Cur-loaded emulsion-filled hydrogel beads showed a higher antioxidant activity than that of pure Cur, effectively delaying the photodegradation of Cur. In addition, the beads had better stability in aqueous and acidic environments, which was favorable for prolonging the release of Cur. These results suggest that the emulsion-filled hydrogel beads have great potential for the delivery of lipophilic bioactive molecules.

Exploring the Properties of Unilamellar Vesicle Bilayers Formed by Ionic Liquid Surfactants for Future Applications in Nanomedicine.

Two ionic liquids (ILs) with amphiphilic properties composed of 1-butyl-3-methylimidazolium dioctylsulfosuccinate (bmim-AOT) and 1-hexyl-3-methylimidazolium dioctylsulfosuccinate (hmim-AOT) form unilamellar vesicles spontaneously simply by dissolving the IL-like surfactant in water. These novel vesicles were characterized using two different and highly sensitive fluorescent probes: 6-propionyl-2-(dimethylaminonaphthalene) (PRODAN) and trans-4-[4-(dimethylamino)-styryl]-1-methylpyridinium iodide (HC). These fluorescent probes provide information about the physicochemical properties of the bilayer, such as micropolarity, microviscosity, and electron-donor capacity. In addition, the biocompatibility of these vesicles with the blood medium was evaluated, and their toxicity was determined using Dictyostelium discoideum amoebas. First, using PRODAN and HC, it was found that the bilayer composition and the chemical structure of the ions at the interface produced differences between both amphiphiles, making the vesicles different. Thus, the bilayer of hmim-AOT vesicles is less polar, more rigid, and has a lower electron-donor capacity than those made by bmim-AOT. Finally, the results obtained from the hemolysis studies and the growth behavior of unicellular amoebas, particularly utilizing the D. discoideum assay, showed that both vesicular systems do not produce toxic effects up to a concentration of 0.02 mg/mL. This elegant assay, devoid of animal usage, highlights the potential of these newly organized systems for the delivery of drugs and bioactive molecules of different polarities.

Arginine-Rich Cell-Penetrating Peptides Induce Lipid Rearrangements for Their Active Translocation across Laterally Heterogeneous Membranes.

Arginine-rich cell-penetrating peptides (CPPs) have emerged as valuable tools for the intracellular delivery of bioactive molecules, but their membrane perturbation during cell penetration is not fully understood. Here, nona-arginine (R9)-mediated membrane reorganization that facilitates the translocation of peptides across laterally heterogeneous membranes is directly visualized. The electrostatic binding of cationic R9 to anionic phosphatidylserine (PS)-enriched domains on a freestanding lipid bilayer induces lateral lipid rearrangements; in particular, in real-time it is observed that R9 fluidizes PS-rich liquid-ordered (Lo) domains into liquid-disordered (Ld) domains, resulting in the membrane permeabilization. The experiments with giant unilamellar vesicles (GUVs) confirm the preferential translocation of R9 through Ld domains without pore formation, even when Lo domains are more negatively charged. Indeed, whenever R9 comes into contact with negatively charged Lo domains, it dissolves the Lo domains first, promoting translocation across phase-separated membranes. Collectively, the findings imply that arginine-rich CPPs modulate lateral membrane heterogeneity, including membrane fluidization, as one of the fundamental processes for their effective cell penetration across densely packed lipid bilayers.

Sunflower Pollen-Morphology Mimicked Spiky Zinc Nanomotors as a Photosensitizer for Killing Bacteria and Cancer Cells.

Photosensitizing agents have received increased attention from the medical community, owing to their higher photothermal efficiency, induction of hyperthermia, and sustained delivery of bioactive molecules to their targets. Micro/nanorobots can be used as ideal photosensitizing agents by utilizing various physical stimuli for the targeted killing of pathogens (e.g., bacteria) and cancer cells. Herein, we report sunflower-pollen-inspired spiky zinc oxide (s-ZnO)-based nanorobots that effectively kill bacteria and cancer cells under near-infrared (NIR) light irradiation. The as-fabricated s-ZnO was modified with a catechol-containing photothermal agent, polydopamine (PDA), to improve its NIR-responsive properties, followed by the addition of antimicrobial (e.g., tetracycline/TCN) and anticancer (e.g., doxorubicin/DOX) drugs. The fabricated s-ZnO/PDA@Drug nanobots exhibited unique locomotory behavior with an average speed ranging from 13 to 14 μm/s under 2.0 W/cm2 NIR light irradiation. Moreover, the s-ZnO/PDA@TCN nanobots exhibited superior antibacterial activity against E. coli and S. epidermidis under NIR irradiation. The s-ZnO/PDA@DOX nanobots also displayed sufficient reactive oxygen species (ROS) amplification in B16F10 melanoma cells and induced apoptosis under NIR light, indicating their therapeutic efficacy. We hope the sunflower pollen-inspired s-ZnO nanorobots have tremendous potential in biomedical engineering from the phototherapy perspective, with the hope to reduce pathogen infections.

3D 프린팅 기술 기반 콘 타입의 신축성 경피약물전달 마이크로니들 패치 개발

This study explored the potential of microneedle technology in transdermal drug delivery application based on a one-step fabrication process using digital light-processing (DLP) printing. To fabricate high-resolution microneedles, DLP printing parameters which include the printing angle were optimized from 0°, 40° and 60° in x-axes. The microneedle substrate was optimized to maintain high stretchability and durability to adapt to dynamic deformations resulting from human movement. The fabricated microneedle demonstrated good ability to effectively penetrate the artificial skin, releasing Rhodamine B as the therapeutic drug molecule in this study. This one-step DLP fabrication process is efficient and versatile, enabling the rapid development of wearable devices for transdermal Drug Deliv. These results emphasize the potential of microneedle technology for creating wearable devices that facilitate convenient, pain-free, and effective delivery of various bioactive molecules for both self-administration and clinical applications.

Innovative Diagnosis and Therapeutic Modalities: Engineered Exosomes in Autoimmune Disease.

Autoimmune diseases refer to a group of conditions where the immune system produces an immune response against self-antigens, resulting in tissue damage. These diseases have profound impacts on the health of patients. In recent years, with the rapid development in the field of biomedicine, engineered exosomes have emerged as a noteworthy class of biogenic nanoparticles. By precisely manipulating the cargo and surface markers of exosomes, engineered exosomes have gained enhanced anti-inflammatory, immunomodulatory, and tissue reparative abilities, providing new prospects for the treatment of autoimmune diseases. Engineered exosomes not only facilitate the efficient delivery of bioactive molecules including nucleic acids, proteins, and cytokines, but also possess the capability to modulate immune cell functions, suppress inflammation, and restore immune homeostasis. This review mainly focuses on the applications of engineered exosomes in several typical autoimmune diseases. Additionally, this article comprehensively summarizes the current approaches for modification and engineering of exosomes and outlines their prospects in clinical applications. In conclusion, engineered exosomes, as an innovative therapeutic approach, hold promise for the management of autoimmune diseases. However, while significant progress has been made, further rigorous research is still needed to address the challenges that engineered exosomes may encounter in the therapeutic intervention process, in order to facilitate their successful translation into clinical practice and ultimately benefit a broader population of patients.

Fabrication and characterization of polydopamine-mediated zein-based nanoparticle for delivery of bioactive molecules

In this study, a combination of whey protein (hydrophilic coating) and polydopamine (crosslinking agent) was used to improve the stability and functionality of quercetin-loaded zein nanoparticles. There are two key benefits of the core-shell nanoparticles formed. First, the ability of the polydopamine to bind to both zein and whey protein facilitates the formation of a stable core-shell structure, thereby protecting quercetin from any pro-oxidants in the aqueous surroundings. Second, neutral and hydrophilic whey proteins were used for the surface coating of the nanoparticles to further enhance the sustained and slow release of quercetin, facilitating its sustained release into the body at a slow and steady rate. The results of this study will promote the innovative development of precise nutritional delivery systems for zein and provide a theoretical basis for the design and development of dietary supplements based on hydrophobic food nutrient molecules.

Preparation, stability and controlled release properties of starch-based micelles for oral delivery of hydrophobic bioactive molecules

Amphiphilic starches incorporating fatty acid ester chains of varying lengths and degrees of substitution (DS) were synthesized to fabricate starch-based micelles for oral delivery of hydrophobic bioactive molecules. The assembly of the amphiphilic starches is influenced by the concentration, temperature, and the chain length and DS of their fatty acid ester chain. Highly acidic environment can hydrolyze the amphiphilic starches, resulting in the formation of small-sized micelles. Conversely, high ionic concentration hinders the self-assembly of amphiphilic starches and the digestive fluids can dilute the amphiphilic starches concentration, leading to the micelle dissociation. However, amphiphilic starches with longer chain length and/or higher DS of the fatty acid ester chain possess greater hydrophobicity, enhancing the stability of starch-based micelles under varying conditions and favouring the protection of Trp-2 peptides during storage. The micelles demonstrate high cell bioaccessibility for Trp-2 peptides, with 59.25 % of Trp-2 peptides being transferred by the intestinal epithelium. These findings suggest a potential starch-based micelle system can be adjusted for the oral delivery of hydrophobic bioactive molecules.

Recent Excavation of Nanoethosomes in Current Drug Delivery.

In the current era, the Transdermal delivery of bioactive molecules has become an area of research interest. The transdermal route of administration enables direct entry of bioactive molecules into the systemic circulation with better and easy accessibility, bypassing the hepatic metabolism and improving patient compliance. Permeation through the skin has always been a barrier. To overcome this challenge, an efficient route by the vesicular system has been adopted so as to have better skin permeation of the bioactive molecules. A novel vesicular and non-invasive drug delivery system called Nanoethosomes was developed. Nanoethosomes are lipid-based vesicular carriers that are used for deeper permeation of the bioactive agents into the skin. The main components of Nanoethosomes are Phospholipids, water, and ethanol. High ethanol concentration in Nanoethosomes distinguishes them from other nano-formulation and results in deeper permeation and smaller vesicular size. This review article gives detailed information on the formulation techniques, and characterization parameters of nanoethosomes along with the research work done by various researchers in the same field. The compiled manuscript gives detailed elaboration about the various drugs used to treat different diseases which when incorporated in nanoethosomes resulted in better permeability and enhanced bioavailability.

Hydrogel-Functionalized Bandages with Janus Wettability for Efficient Unidirectional Drug Delivery and Wound Care.

Chronic wounds have imposed a severe physical and economic burden on the global healthcare system, which are usually treated by the delivery of drugs or bioactive molecules to the wound bed through wound dressings. In this work, we have demonstrated a hydrogel-functionalized bandage with Janus wettability in a bilayer structure to achieve unidirectional drug delivery and multifunctional wound care. The Janus patterned bandage with porous gradient wetting channels on the upper layer is responsible for the unidirectional transport of the drug from the outside to the wound bed (up to 90% drug transport efficiency) while preventing drug diffusion in unwanted directions (<8%). The hydrogel composed of chitosan quaternary ammonium salt (HACC), poly(vinyl alcohol) (PVA), and poly(acrylic acid) (PAA) at the bottom layer further functionalized such a bandage with biocompatibility, excellent antibacterial properties, and hemostatic ability to promote wound healing. Especially, the hydrogel-functionalized bandage with Janus wettability exhibits excellent mechanical flexibility (∼198% strain), which can comply well with skin deformation (stretching, bending, or twisting) and maintain unidirectional drug delivery behavior without any leakage. The in vivo full-thickness skin wound model confirms that the hydrogel-functionalized bandage can significantly facilitate epithelialization and collagen deposition and improve drug delivery efficiency, thus promoting wound closure and healing (the wound healing ratio was 98.10% at day 15). Such a synergistic strategy of unidirectional drug delivery and multifunctional wound care provides a more efficient, economical, and direct method to promote wound healing, which could be used as a potential high-performance wound dressing for clinical application.

Lipid-based nanocarriers for enhanced delivery of plant-derived bioactive molecules: a comprehensive review.

Bioactive compounds derived from plants have been investigated for treating various pathological conditions. However, the utilization of these compounds has challenges such as instability, low solubility and bioavailability. To overcome these challenges, the encapsulation of bioactive molecules with in a novel nano carrier system enabling effective delivery and clinical translation has become essential. Lipid-based nanocarriers provide versatile platforms for encapsulating and delivering bioactive compounds and overcome the challenges. These novel carriers can improve solubility, stability, improved drug retention and therapeutic efficacy of plant derived bioactive compounds. The current review evaluates the challenges in delivery of plant bioactives and highlights the potential of various lipid-based nano carriers designed to improve its therapeutic efficacy.

M2 Macrophage-Derived Small Extracellular Vesicles Ameliorate Pyroptosis and Intervertebral Disc Degeneration.

Intervertebral discs (IVDs) have a limited self-regenerative capacity and current strategies for IVD regeneration are unsatisfactory. Recent studies showed that small extracellular vesicles derived from M2 macrophage cells (M2-sEVs) inhibited inflammation by delivery of various bioactive molecules to recipient cells, which indicated that M2-sEVs may offer a therapeutic strategy for the repair of IVDs. Herein, we investigated the roles and mechanisms of M2-sEVs on IVD regeneration. The invitro results demonstrated that M2-sEVs inhibited pyroptosis, preserved cellular viability, and promoted migration of nucleus pulposus cells (NPCs). Bioinformatics analysis and verification experiments of microRNA (miR) expression showed that miR-221-3p was highly expressed in M2-sEVs. The mechanism of action was explored and indicated that M2-sEVs inhibited pyroptosis of NPCs through transfer of miR-221-3p, which suppressed the expression levels of phosphatase and tensin homolog and NOD-, LRR-, and pyrin domain-containing protein 3. Moreover, we fabricated decellularized ECM-hydrogel (dECM) for sustained release of M2-sEVs, which exhibited biocompatibility and controlled release properties. The invivo results revealed that dECM-hydrogel containing M2-sEVs (dECM/M2-sEVs) delayed the degeneration of intervertebral disc degeneration (IDD) models. In addition to demonstrating a promising therapeutic for IDD, this study provided valuable data for furthering the understanding of the roles and mechanisms of M2-sEVs in IVD regeneration.