One‐Stone‐Three‐Birds Biomimetic Oral Targeting Delivery Strategy for On‐Demand Controlled Drug Release and Intervertebral Disc Degeneration Therapy

Intervertebral disc degeneration (IDD) is a multifactorial condition characterized by excessive inflammation, immune dysfunction, and metabolic disorders. Current therapeutic strategies primarily rely on local injection, a traumatic approach associated with risks of tissue damage and infection. Therefore, developing safer, non-invasive, and precisely targeted drug delivery systems capable of multi-targeted interventions for the degenerating nucleus pulposus remains a significant challenge in IDD treatment. In this study, we designed a novel biomimetic oral delivery system featuring targeted drug delivery to degenerated intervertebral discs (IVDs) and on-demand drug release. This system utilizes yeast microcapsules (YC) and reactive oxygen species (ROS)-responsive nanoparticles to deliver Celastrol (Cel), a bioactive compound derived from traditional Chinese medicine. After oral administration, the system achieves targeted transport to IVDs through macrophage "hitchhiking," where the inflammatory microenvironment rich in ROS triggers accelerated Cel release. Importantly, this strategy embodies a "One-Stone-Three-Birds" therapeutic approach, simultaneously exerting multi-targeted biological effects: inhibiting inflammasome activation, reprogramming macrophage polarization, and modulating lipid metabolism. These synergistic actions reverse the adverse degenerative microenvironment of the nucleus pulposus, promote tissue regeneration, and effectively suppress the progression of IDD. This research presents a novel, non-invasive oral targeted delivery strategy for IDD treatment, integrating biomimetic engineering with on-demand drug release. This innovative approach offers a comprehensive framework for microenvironmental remodeling and provides new insights into intervertebral disc regeneration.