Sequential delivery of STING inhibitor and rapamycin by a Sr-Zn mesoporous bioactive glass platform for spinal cord injury repair.

Spinal cord injury (SCI) leads to permanent neurological deficits, primarily due to immune dysregulation following trauma. Current biomaterial-based interventions often fail to address the dual need for acute inflammation control and long-term immune tolerance. Herein, we present a multifunctional Sr-Zn mesoporous bioactive glass (MBG) system that enables spatiotemporal immunoreprogramming. Rapamycin (Ra) is first loaded into MBG pores to induce Treg differentiation via mTOR inhibition. STING inhibitor H-151 is then adsorbed onto a polydopamine (PDA) coating for early suppression of cGAS-STING signaling. Finally, a CCL22-mimetic peptide is grafted for CCR4-mediated Treg recruitment. Meanwhile, sustained Sr2+/Zn2+ release provides bioactive ionic cues that support immune remodeling and neural repair. This sequential design first polarizes microglia/macrophages toward an anti-inflammatory M2 phenotype and then enriches Tregs to sustain an immunosuppressive niche, while concurrently facilitating neuroregenerative remodeling. In vitro, the system regulates STING and mTOR pathways, induces Treg generation, and enhances neural stem cell differentiation and neuronal outgrowth. In a mouse SCI model, the injectable MBG-hydrogel hybrid reduces lesion volume, promotes remyelination, axonal regrowth, and motor function. Treg depletion or CCR4 blockade abrogates therapeutic benefits, confirming the role of adaptive immunity. This study offers a dual-arm immunoengineering strategy that couples innate suppression and adaptive tolerance, opening new avenues for CNS regeneration.