Anti‐Inflammatory and Neuroactive Effects of Polymer‐Coated Iron Oxide Nanoparticles Functionalized With Interleukin 4 for Spinal Cord Injury

Inflammation plays a pivotal role in a plethora of pathological processes, including spinal cord injury (SCI). However, effective anti-inflammatory therapies for complex central nervous system pathologies remain an unmet clinical need. Herein, we present polymer-coated iron oxide nanoparticles (IONPs) as an unprecedented platform combining bioactive coatings, an IL-4 payload, and superparamagnetic properties validated on relevant in vitro and in vivo models. We demonstrate significant neuroactive and anti-inflammatory actions driven by IONPs-IL4 in comparison to soluble IL-4. Interestingly, both hyaluronic acid-coated and chitosan-coated IONPs functionalized with IL-4 (C12/HA-IL4 and C12/CHI-IL4, respectively) preserve maturation features and enhance firing frequency in primary neurons, while decreasing pro-inflammatory markers in macrophages. In microglia cells, they decrease TNF-α and increase Arg-1 and CD206. Importantly, non-functionalized IONPs also display a beneficial impact on neurons and macrophages. These nanoparticles can be successfully embedded into 3D porous reduced graphene oxide (rGO) scaffolds, retaining effective anti-inflammatory properties in vitro. When examined in a chronic rat SCI model, rGO carrying C12/HA-IL4 adequately integrates into the lesion, reduces vimentin at the interfaces, and facilitates total body weight recovery. These promising data encourage further investigation into the therapeutic potential of these nanosystems for SCI, thus paving the way for advanced SCI nanotherapeutics.