Enhancing spinal cord injury recovery with functional liposomal nanomedicine: A neuroprotective and anti-inflammatory approach

Background

Spinal cord injury (SCI) triggers severe secondary damage and persistent neurological deficits, exemplified by unacceptably high functional loss where >80 % of patients experience irreversible lower limb paralysis with <20 % achieving meaningful recovery, driven by pro-inflammatory M1 microglia that secrete inflammatory cytokines and reactive oxygen species (ROS). Thalidomide’s anti-inflammatory potential is hindered by low bioavailability and systemic toxicity, necessitating targeted delivery strategies to address this unmet Level 1 clinical need for restoring acceptable function in specific SCI scenarios.

Methods

To address these challenges, we developed RLNPP@Tha, a CD44-targeted, ROS-responsive liposomal nanomedicine, to selectively deliver thalidomide to the SCI microenvironment. RLNPP@Tha’s physicochemical properties, drug release, cellular uptake, and anti-inflammatory/neuroprotective effects were characterized in vitro. Its therapeutic efficacy, including locomotor recovery, inflammation modulation, tissue repair, and biosafety, was evaluated in a rat SCI model.

Results

RLNPP@Tha exhibited ROS-dependent thalidomide release (92 % at 400 μM H₂O₂ in 12 h) and selective uptake by activated BV2 microglia. In vitro, it reduced intracellular ROS by ∼70 %, suppressed pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) by 50–70 %, and protected SH-SY5Y neurons from oxidative apoptosis (85 % viability vs. 30 % in controls). In vivo, RLNPP@Tha improved Basso-Beattie-Bresnahan (BBB) scores to 18–19 (vs. 5–6 for saline), reduced cytokine levels by 45–60 %, preserved spinal cord morphology, enhanced neuronal survival, inhibited glial scarring, and promoted M2 microglial polarization. Biosafety assessments confirmed minimal systemic toxicity.

Conclusion

RLNPP@Tha’s dual CD44/ROS-responsive mechanism enables precise modulation of the SCI inflammatory microenvironment, providing sufficient improvements in secondary injury markers (Levels 2–4 of the design constraint hierarchy) to potentially address Level 1 clinical challenges, such as unacceptable functional loss in moderate contusion SCI cases. This nanomedicine offers preliminary evidence toward solving unmet needs in neuroprotection, paving the way for advanced targeted therapies.