Controlled release of MIF siRNA and GDNF protein from a photocurable scaffold efficiently repairs spinal cord injury

Compared with traditional treatment strategies, siRNA-based gene therapy combines with protein therapy to offer a new strategy for spinal cord injury (SCI). The siRNA and protein therapy are limited by the large and deep lesion site and local co-delivery vectors. However, the photocurable scaffold has the properties of injectable, flexible, and biodegradable, which provide a potential formulation for siRNA and protein combined therapy. Here, a photocurable lipid nanoparticle gel (PLNG) scaffold is designed for efficiently sustained and controlled release of the macrophage migration-inhibitory factor (MIF) targeted siRNA and co-delivery of GDNF protein for SCI. The GDNF is chemically modified in the scaffold and the prepared GDNF-PLNG/siRNA scaffold is injectable with easily photocured. This formulation can inhibit inflammation by promoting macrophage M2 polarization and effectively promote primary neuron axon growth. After locally administered with GDNF-PLNG/siMIF scaffold to SCI mice, the scaffold promoted neuron regeneration by upregulation of neuron cytokine production and inhibited inflammation through the downregulation immune pathway. With the interaction mechanism of GDNF and MIF siRNA, GDNF-PLNG/siMIF scaffold increases the collagen and integrin expression to promote spinal cord repairing and significantly improve motor function, so that scaffold is a potential candidate gene formulation applied to clinical SCI treatment.