Click chemistry-conjugated protein-drug micelles with anti-ferroptotic and anti-inflammatory properties promote regeneration in spinal cord injury

•A new formulation engineering strategies for promoting regeneration in spinal cord injury.•Click chemistry conjugated therapeutic proteins and insoluble small molecular drugs.•A platform for integrating macromolecules and insoluble small molecular drugs for biomedical applications. Spinal cord injury (SCI) can disrupt neural circuitry and connectivity, leading to neurological and motor disabilities. Functional recovery relies on neuroplasticity and injured axon regeneration to rebuild connections and circuits. Current drugs with potential neuropharmacological effects are rapidly metabolized after systemic administration, reducing their pharmaceutical activity. Thus, efficient treatment of SCI remains a challenge. In this study, we designed click chemistry-conjugated protein-drug micelles (FPAaF) by the conjugation of insoluble ferrostatin-1 (Fer-1) and dibenzocyclooctyne (DBCO) modules to amphiphilic polymers, followed by click chemistry assembly with pH-responsive azido linker-modified acidic fibroblast growth factor (aFGF). SCI rats receiving systemic administration of FPAaF showed improved blood circulation and enhanced accumulation in the spinal cord. In vitro and in vivo studies showed the anti-ferroptotic and anti-inflammatory effects of FPAaF micelles. Moreover, significant improvements in neural and motor recovery were achieved upon the release of Fer-1 and aFGF in the acidic SCI microenvironment, which resulted in anti-ferroptotic and anti-inflammatory activities. This study shows that Fer-1 and aFGF conjugated micelles may exert their synergistic pharmacological effects on SCIs, suggesting that this is a promising strategy for the treatment of as-yet-incurable diseases.