After spinal cord injury (SCI), successive systemic administration
of microtubule-stabilizing agents has been shown to promote axon regeneration.
However, this approach is limited by poor drug bioavailability, especially
given the rapid restoration of the blood–spinal cord barrier.
There is a pressing need for long-acting formulations of microtubule-stabilizing
agents in treating SCI. Here, we conjugated the antioxidant idebenone
with microtubule-stabilizing paclitaxel to create a heterodimeric
paclitaxel–idebenone prodrug via an acid-activatable, self-immolative
ketal linker and then fabricated it into chondroitin sulfate proteoglycan-binding
nanomedicine, enabling drug retention within the spinal cord for at
least 2 weeks and notable enhancement in hindlimb motor function and
axon regeneration after a single intraspinal administration. Additional
investigations uncovered that idebenone can suppress the activation
of microglia and neuronal ferroptosis, thereby amplifying the therapeutic
effect of paclitaxel. This prodrug-based nanomedicine simultaneously
accomplishes neuroprotection and axon regeneration, offering a promising
therapeutic strategy for SCI.