Injectable exosome-functionalized extracellular matrix hydrogel for metabolism balance and pyroptosis regulation in intervertebral disc degeneration

Exosome therapy is a promising therapeutic approach for intervertebral disc degeneration (IVDD) and achieves its therapeutic effects by regulating metabolic disorders, the microenvironment and cell homeostasis with the sustained release of microRNAs, proteins, and transcription factors. However, the rapid clearance and disruption of exosomes are the two major challenges for the application of exosome therapy in IVDD. Herein, a thermosensitive acellular extracellular matrix (ECM) hydrogel coupled with adipose-derived mesenchymal stem cell (ADSC) exosomes (dECM@exo) that inherits the superior properties of nucleus pulposus tissue and ADSCs was fabricated to ameliorate IVDD. This thermosensitive dECM@exo hydrogel system can provide not only in situ gelation to replenish ECM leakage in nucleus pulposus cells (NPCs) but also an environment for the growth of NPCs. In addition, sustained release of ADSC-derived exosomes from this system regulates matrix synthesis and degradation by regulating matrix metalloproteinases (MMPs) and inhibits pyroptosis by mitigating the inflammatory response in vitro. Animal results demonstrated that the dECM@exo hydrogel system maintained early IVD microenvironment homeostasis and ameliorated IVDD. This functional system can serve as a powerful platform for IVD drug delivery and biotherapy and an alternative therapy for IVDD.

Automated summary

Exosome therapy is a promising approach for treating intervertebral disc degeneration (IVDD) by regulating metabolic disorders, the microenvironment, and cell homeostasis through sustained release of microRNAs, proteins, and transcription factors. The thermosensitive dECM@exo hydrogel system, coupled with adipose-derived mesenchymal stem cell exosomes, provides in situ gelation to replenish ECM leakage in nucleus pulposus cells and environment for their growth, while regulating matrix synthesis, degradation, and inhibiting inflammatory responses. Animal studies show that this system helps maintain early IVD microenvironment homeostasis and can potentially serve as a powerful platform for drug delivery and therapy for IVDD.