Biomimetic KeMA hydrogel with CAP-EVs-MEF2C inhibits inflammation and senescence in intervertebral disc degeneration

Intervertebral disc degeneration (IVDD) is a major cause of chronic back pain, characterized by progressive structural breakdown, inflammation, and cellular senescence within the disc. Current treatments often provide symptomatic relief but fail to address the underlying degenerative processes or restore disc structure. A key challenge is the poor targeting and retention of therapeutic agents within the avascular disc. Modulating cellular pathways like MEF2C/P21/CDK2 offers a promising strategy to combat inflammation in cartilaginous endplate chondrocytes (CEPCs) and senescence in nucleus pulposus cells (NPCs), which are critical drivers of IVDD progression.

Researchers developed a novel biomimetic KeMA hydrogel encapsulating cartilage-affinity peptide (CAP)-modified extracellular vesicles (EVs) derived from MEF2C-overexpressing macrophages, termed KeMA@CAP-EVs-MEF2C. The study aimed to evaluate this system's ability to modulate the MEF2C/P21/CDK2 axis. Initial investigations involved single-cell RNA sequencing (scRNA-seq) to identify MEF2C as a key regulator. The hydrogel's delivery and sustained-release properties were assessed. Finally, the therapeutic efficacy of the KeMA@CAP-EVs-MEF2C system was validated through in vivo studies in an IVDD model, focusing on cellular senescence and structural restoration.

Single-cell RNA sequencing (scRNA-seq) identified MEF2C as a pivotal regulator in disc cells, demonstrating its capacity to upregulate p21 and suppress CDK2. This specific modulation of the MEF2C/P21/CDK2 axis was found to effectively reduce inflammation in cartilaginous endplate chondrocytes (CEPCs) and attenuate cellular senescence in nucleus pulposus cells (NPCs). The engineered CAP-modified extracellular vesicles (EVs) within the KeMA hydrogel exhibited significantly enhanced delivery efficiency and superior sustained-release characteristics, crucial for prolonged therapeutic action within the challenging disc environment.

In vivo validation confirmed the therapeutic potential of the KeMA@CAP-EVs-MEF2C system, showing effective mitigation of cellular senescence and promoting substantial structural restoration in models of intervertebral disc degeneration (IVDD). While the abstract highlights significant qualitative improvements, specific numerical data, such as percentages of reduction or p-values for these findings, were not provided.