Enhanced Mitochondrial Targeting and Inhibition of Pyroptosis with Multifunctional Metallopolyphenol Nanoparticles in Intervertebral Disc Degeneration

Abstract Intervertebral disc degeneration (IVDD) is a significant contributor to low back pain, characterized by excessive reactive oxygen species generation and inflammation‐induced pyroptosis. Unfortunately, there are currently no specific molecules or materials available to effectively delay IVDD. This study develops a multifunctional full name of PG@Cu nanoparticle network (PG@Cu). A designed pentapeptide, bonded on PG@Cu nanoparticles via a Schiff base bond, imparts multifunctionality to the metal polyphenol particles (PG@Cu‐FP). PG@Cu‐FP exhibits enhanced escape from lysosomal capture, enabling efficient targeting of mitochondria to scavenge excess reactive oxygen species. The scavenging activity against reactive oxygen species originates from the polyphenol‐based structures within the nanoparticles. Furthermore, Pyroptosis is effectively blocked by inhibiting Gasdermin mediated pore formation and membrane rupture. PG@Cu‐FP successfully reduces the activation of the nucleotide‐binding oligomerization domain‐like receptor family pyrin domain‐containing 3 inflammasome by inhibiting Gasdermin protein family (Gasdermin D, GSDMD) oligomerization, leading to reduced expression of Nod‐like receptors. This multifaceted approach demonstrates higher efficiency in inhibiting Pyroptosis. Experimental results confirm that PG@Cu‐FP preserves disc height, retains water content, and preserves tissue structure. These findings highlight the potential of PG@Cu‐FP in improving IVDD and provide novel insights for future research in IVDD treatments.