Nuciferine-Loaded Lipid Nanoparticle Microneedles Alleviate Intervertebral Disc Degeneration by Restoring Nucleus...

Background/Objectives: Intervertebral disc degeneration (IDD) is a major cause of chronic low back pain and disability. Nuciferine, a natural alkaloid with mitochondrial protective activity, shows therapeutic potential for IDD. However, the avascular nature of intervertebral discs limits effective drug delivery. This study aimed to develop a hierarchical stimuli-responsive microneedle (MN) system for localized nuciferine delivery. Methods: Nuciferine-loaded lipid nanoparticles (LNPs) were embedded in a phenylboronic acid-modified hyaluronic acid (HA-PBA) matrix to construct functional MNs. LNP characteristics and drug release were evaluated under physiological and simulated degenerative conditions. The effects of released LNPs on nucleus pulposus cell (NPC) viability, mitophagy, oxidative stress, and extracellular matrix homeostasis were assessed in vitro. Therapeutic efficacy was further evaluated in a rat IDD model. Results: Nuciferine-loaded LNPs had a mean size of 86.54 nm, PDI of 0.108, and encapsulation efficiency of 75.65%. The HA-PBA MNs showed minimal drug release at pH 7.4 but markedly accelerated release under dual stimuli (100 μM H₂O₂ and pH 5.0). Released LNPs maintained NPC viability above 90%, enhanced mitophagy by increasing LC3B-II and decreasing P62, and alleviated oxidative damage and extracellular matrix imbalance. In vivo, MN treatment significantly preserved the disc height index and improved Pfirrmann grades compared with the IDD group (p < 0.05). Conclusions: The hierarchical stimuli-responsive MN system enables localized, pathological microenvironment-responsive nuciferine delivery and protects against IDD by promoting mitophagy, reducing oxidative damage, and restoring extracellular matrix homeostasis. This strategy provides a potential approach for localized treatment of IDD.