NEP-modified human serum albumin nanoparticles enhance the therapeutic effect of methylprednisolone against spinal cord injury.

Background: Frequent injection of high-dose methylprednisolone (MP) is used to treat spinal cord injury (SCI), but free MP is associated with various side effects and its water solubility is low, limiting potential dosing regimes and administration routes. Albumin-based nanoparticles, which can encapsulate therapeutic drugs and release cargo in a controlled pattern, show high biocompatibility and low toxicity. The Nogo protein, expressed on the surface of oligodendrocytes, can inhibit axonal growth by binding with the axonal Nogo receptor (NgR). Peptide NEP, an NgR antagonist, can bind specifically to Nogo, significantly improving functional recovery and axon growth in the corticospinal tract. Therefore, we hypothesized that delivering MP within nanoparticles decorated with NEP could avoid the disadvantages of free MP and enhance its therapeutic efficacy against SCI.

Results: We used human serum albumin to prepare MP-loaded NPs (MP-NPs), to whose surface we conjugated NEP to form NEP-MP-NPs. Transmission electron microscopy indicated successful formation of nanoparticles. NEP-MP-NPs were taken up significantly better than MP-NPs by the Nogo-positive cell line RSC-96 and were associated with significantly higher Basso-Beattie-Bresnahan locomotor scores in rats recovering from SCI. Micro-computed tomography assay showed that NEP-MP-NPs mitigated SCI-associated loss of bone mineral density and accelerated spinal cord repair.

Conclusions: NEP-MP-NPs can enhance the therapeutic effects of MP against SCI. This novel platform may also be useful for delivering other types of drugs.