Systemic delivery of drug-free polymeric nanoparticles reprograms innate immunity in a sex-dependent manner after spinal cord injury

Sex differences influence distinct inflammatory responses after spinal cord injury (SCI), yet their impact on immune-modulating nanotherapeutics remains unclear. Here, we investigated the sex-dependent effects of drug-free poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) following SCI. Systemic NP administration enhanced locomotor recovery in both sexes and eliminated the functional gap observed in controls. Mechanistically, NPs engaged distinct immune pathways between sexes. Females accumulated more NPs in the spleen, leading to reduced monocyte-derived macrophage infiltration, whereas males showed greater NP accumulation at the lesion and attenuated microglial activation. Transcriptomic analysis showed preferential modulation of eicosanoid-related pathways in females and NF-κB-linked signaling in males. These sex-specific, yet convergent NPs-induced immunomodulatory effects reduced fibrotic scarring and enhanced remyelination, with females showing greater Schwann cell-mediated repair and males exhibiting marked suppression of microglial activation. Collectively, these findings demonstrate that NPs promote comparable functional recovery in both sexes through distinct, sex-influenced immune mechanisms and establish a translational framework for sex-informed immune targeting and nanotherapeutic design in SCI and other inflammation-mediated diseases.