A “Progenitor Cell Ark” hydrogel system for intervertebral disc regeneration via mitochondrial targeting and mitophagy enhancement

Abstract

Intervertebral disc degeneration (IVDD), driven by progenitor cell loss and oxidative stress, remains a major clinical challenge with limited effective regenerative therapies. Here, we present a “Progenitor Cell Ark,” a triple-layered hydrogel microsphere system designed for synergistic cell delivery and microenvironment remediation. The Ark comprises an outer nucleus pulposus progenitor cell (NPPC) layer for cell replenishment, a middle GelMA/HAMA scaffold for support, and an inner SS31-modified ultrasmall Prussian blue nanozyme (SS31-UPN) layer that specifically targets mitochondria to scavenge ROS and promote mitophagy. In vitro, SS31-UPN effectively protected NPPCs from oxidative damage, restored mitochondrial function, and enhanced mitophagy. Critically, in severe IVDD rat models, the Progenitor Cell Ark significantly improved intervertebral disc structure, promoted neo-tissue formation, and restored biomechanical function, outperforming cell or bioscaffold therapy alone. Mechanistically, we demonstrate that SS31-UPN’s mitochondrial targeting enhances mitophagy, drives ECM and energy metabolic remodeling, and preserves NPPC stemness, thereby creating a proregenerative milieu. This integrated “cell-in-a-box” strategy offers a robust platform for reversing IVDD and holds notable translational potential for regenerative medicine.