Sustained and Bioresponsive Two‐Stage Delivery of Therapeutic miRNA via Polyplex Micelle‐Loaded Injectable Hydrogels for Inhibition of Intervertebral Disc Fibrosis

Intervertebral disc degeneration (IDD) is frequently caused by gradual pathological changes inside intervertebral discs (IVDs) and progressive fibrosis. MicroRNA-29 (miR-29) family possesses potent fibrosis suppression capability, but their application for treatment of chronic IDD is limited due to lack of suitable local delivery systems. In this report, given various overexpressed matrix metalloproteinases (MMPs) during IDD, injectable MMP-degradable hydrogels encapsulating MMP-responsive polyplex micelles are developed for sustained and bioresponsive delivery of miR-29a into nucleus pulposus cells via a two-stage process. Cationic block copolymers are designed to complex miR-29a, and subsequently mixed with the poly(ethylene glycol) (PEG) gelation precursors and MMP-cleavable peptide cross-linkers for in situ formation of polyplex micelle-encapsulated hydrogels in the diseased IVDs. In the presence of MMPs, the polyplex micelles are first released by MMP cleavage of the hydrogels, and subsequently, MMPs-responsive detachment of PEG shells from polyplex micelles contributes to efficient cellular uptake and endosomal escape. MiR-29a is demonstrated to effectively silence the expression of MMP-2, inhibit the fibrosis process, and reverse IDD in animal models through blocking the β-catenin translocation pathway from the cytoplasm to the nucleus. This two-stage bioresponsive local miRNA delivery system represents a novel and promising strategy for the treatment of chronic IDD.