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

2026 · doi:10.64898/2026.03.06.709912
preprint OA: closed CC-BY-NC-ND-4.0
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The paper studied how systemic delivery of drug-free PLGA polymeric nanoparticles affects immune responses and functional recovery after spinal cord injury in male versus female animals, using in vivo administration followed by locomotor testing, immune-cell infiltration/activation assessment, and transcriptomic pathway analysis. The authors found that nanoparticles enhanced locomotor recovery in both sexes and eliminated an existing functional gap seen in controls, but they did so via sex-dependent immune mechanisms: females accumulated more nanoparticles in the spleen with reduced monocyte-derived macrophage infiltration and preferential modulation of eicosanoid-related pathways, while males showed greater nanoparticle accumulation at the lesion with attenuated microglial activation and NF-κB-linked signaling changes. These immunomodulatory effects coincided with reduced fibrotic scarring and enhanced remyelination, with females showing greater Schwann cell-mediated repair and males showing stronger suppression of microglial activation. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

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. Graphic Abstract
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Abstract 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. Competing Interest Statement The authors have declared no competing interest.

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License: CC-BY-NC-ND-4.0