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Development of Recombinant Anti-TLR2 Antibodies and PLGA Nanoparticle-based Gene Therapy for the Treatment of Neuropathic Pain

Lee, S.; Jeon, J.; Lee, H.; Barcelona, E. E.; Hong, J.; Lee, S. J.

2025-11-14 neuroscience
10.1101/2025.11.13.688281 bioRxiv
Show abstract

Neuroinflammation is a key contributor to neuropathic pain, with microglial Toll-like receptor 2 (TLR2) playing a central role in initiating and sustaining proinflammatory responses. However, existing TLR2-targeting antibody therapies are limited by poor delivery to the central nervous system and short-lived efficacy. We developed a non-viral gene therapy strategy using biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to deliver recombinant anti-TLR2 antibody genes. High-affinity nanobody and single-chain variable fragment candidates were selected through phage display screening and shown to suppress TLR2-dependent signaling both in vitro and in vivo. In mouse models of neuropathic pain, a single intrathecal administration of PLGA NP-encapsulated antibody genes produced robust and sustained analgesia, accompanied by reduced glial activation and proinflammatory cytokine expression. These findings demonstrate a modular NP-based platform for sustained antibody expression in the central nervous system and establish its potential for the treatment of chronic pain driven by innate immune activation.

Published in Molecular Therapy (predicted rank #4) · training set

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