A Zinc-Citrate Metal–Organic Framework-Based Adaptable Hydrogen Sulfide Delivery System for Regulating Neuroregeneration Microenvironment in Spinal Cord Injury

Spinal cord regeneration is a highly intricate physiological process. A material designed for a single function may struggle to swiftly adapt to a delicate regulatory microenvironment, which can cause delays in nerve regeneration and limit functional recovery. To address this, we have devised a multifunctional tissue engineering approach that uses endogenous reactive oxygen species (ROS) production to trigger the on-demand release of hydrogen sulfide (H2S) at the injury site. This targeted delivery aims to facilitate spinal cord repair, neuroprotection, and neuroregeneration. Our delivery system incorporates a H2S donor (peroxyTCM) with ROS-responsive triggers integrated into a zinc-citrate metal–organic framework (Zn-CA MOF) (PTCM@Zn-CA), which is then encapsulated within a composite hydrogel (GelMA@LAMC). This integrated strategy considerably boosts the regeneration of spinal cord injury (SCI) through the physiological benefits of H2S and zinc ions. Specifically, it can mitigate oxidative stress and inflammation, induce macrophage M2 phenotype polarization, protect nerve cells, promote angiogenesis, and restore mitochondrial function to normalcy. Using pleiotropic messengers in tissue regeneration holds great promise for the effective repair of SCI.