Plant-derived extracellular vesicle-like nanoparticles: an emerging immunomodulatory strategy for intervertebral disc degeneration.

Intervertebral disc degeneration (IDD), a leading driver of chronic low back pain, has become a major socioeconomic and public health burden due to its high disability rate and substantial treatment costs. Accumulating evidence has redefined IDD as an immune-mediated disorder characterized by the breakdown of immune privilege, infiltration of immune cells, and chronic sterile inflammation driven by innate immune pathways including NF-κB and the NLRP3 inflammasome. Current management strategies, including conservative care and surgery, primarily alleviate symptoms but fail to halt disease progression, while biological therapies are often costly. There is a pressing need for effective, accessible interventions. Plant-derived extracellular vesicle-like nanoparticles (PELNs) present a promising alternative. Rich in bioactive components, PELNs have demonstrated pleiotropic benefits in various diseases by exerting anti-inflammatory, antioxidant, and extracellular matrix (ECM)-enhancing activities, and by inhibiting multiple modes of programmed cell death, including apoptosis, pyroptosis, and ferroptosis. Notably, these nanoparticles act as multi-targeted immunomodulators capable of reshaping the local immune microenvironment-suppressing pro-inflammatory cytokine cascades and dampening inflammasome activation, and shifting macrophage polarization from a pro-inflammatory M1 to a tissue-repair M2 phenotype. These multi-targeted mechanisms align closely with the complex pathophysiology of IDD. Although the direct application of PELNs for IDD remains largely unexplored, their mechanistic profile and inherent advantages position them as a novel and compelling therapeutic candidate to prevent or delay IDD. By targeting the core immunopathological drivers of disc degeneration, PELNs offer a unique opportunity to restore immune homeostasis within this otherwise privileged niche.