PLGA nanoparticle-mediated anti-inflammatory gene delivery for the treatment of neuropathic pain

This study aimed to mitigate neuropathic pain behavior in a sciatic nerve transection (SNT)-induced mouse model by delivering anti-inflammatory cytokines - interleukin-4 (IL-4), interleukin-10 (IL-10), and transforming growth factor-beta 1 (TGF-β1) - via poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). Upon gene delivery of IL-4, IL-10, and TGF- β1, the anti-inflammatory effects and induction of microglia M2 polarization were evaluated. Plasmid (IL-4, IL-10, and TGF-β1)-encapsulated PLGA NPs (PLGA@IL-4, PLGA@IL-10, and PLGA@TGF-β1) were synthesized and characterized for size, zeta potential, cellular toxicity, and cellular uptake. The analgesic effect of anti-inflammatory gene delivery using PLGA NPs was then assessed in a mouse model of neuropathic pain. Gene delivery of IL-4, IL-10, and TGF-β1 showed a significant anti-inflammatory effect in LPS-treated cells and IL-4 strongly promoted microglia M2 polarization in vitro. PLGA NPs successfully delivered the anti-inflammatory cytokine-coding genes into mouse spinal cord cells, specifically targeting microglia. PLGA@IL-4, PLGA@IL-10, and PLGA@TGF-β1 NPs produced analgesic effects in a SNT-induced mouse neuropathic pain model. Notably, PLGA@IL-4 demonstrated the most effective and remarkably long-lasting analgesic effect, strongly enhancing microglia M2 polarization in spinal cord microglia. Gene therapy using PLGA NPs for overexpression of anti-inflammatory cytokines could be a promising strategy for the treatment of neuropathic pain.