Near-infrared light-activated nanosystem endows scaffold with controllable nitric oxide release for peripheral nerve...

The photosensitive S-nitrosocysteine (CysNO) could respond to light irradiation to produce nitric oxide (NO), exhibiting tremendous potential in accelerating peripheral nerve regeneration. However, its further application was limited by the burst release of NO and the requirement for ultraviolet excitation with low tissue penetration. Herein, a near-infrared-triggered NO controlled release nanosystem UCNP@ZIF-8/CysNO consisting of an upconversion nanoparticle (UCNP) core and zeolitic imidazolate framework-8 (ZIF-8) shell loading with CysNO was constructed, and then blended with poly-l-lactic acid powder to fabricate nerve scaffold by laser additive manufacturing technique. Once irradiated by near-infrared light, UCNP emitted ultraviolet light, triggering the S-NO cleavage of CysNO to generate NO, thereby achieving deep penetration therapy. In addition, the spatial confinement effect of 2-methylimidazole skeleton structure in ZIF-8 could effectively ensure the controlled release of NO. The Griess method test demonstrated that the scaffold exhibited sustained and stable NO release kinetics, as well as excellent near-infrared controllability. Immunofluorescence staining showed that the released NO upregulated the expression of neuronal markers Nestin and GFAP, indicating that the stem cells differentiated into neurons. Further mechanism revealed that the upregulated marker expression might be attributed to the enhanced Ca²⁺ influx. Consequently, this work might provide a novel perspective for nerve repair.