TRPA1 siRNA-Loaded Nanoformulation Ameliorates Chemotherapy-Induced Peripheral Neuropathy

Small interfering RNA (siRNA) has emerged as a cutting-edge therapeutic strategy, with significant promise for addressing peripheral neuropathies. Despite its immense revolutionary therapeutic potential, the application and sustained release of siRNA for the treatment of chronic pain remain an arduous scientific challenge. This study introduces a novel cationic lipid-based siRNA formulation specifically targeting transient receptor potential ankyrin 1 (TRPA1) for the systemic treatment of chemotherapy-induced neuropathic pain (CINP), a condition with no US-FDA-approved therapeutic options. CINP involves the upregulation of the TRPA1 channel, a key player in nociceptive signaling. Our approach leverages the selective silencing of the TRPA1 gene via siRNA encapsulated in liposomes, offering a targeted and safer therapeutic intervention. The proof-of-principle was established through <i>in vivo</i> experiments, demonstrating significant downregulation of TRPA1 mRNA and protein expressions in the spinal cord following intrathecal administration. Liposomal encapsulation improved siRNA stability and delivery, validated through sophisticated morphometric and analytical techniques. Behavioral assays revealed that both intravenous and intrathecal administrations of this TRPA1 siRNA formulation significantly reduced mechanical and cold hypersensitivity in CINP models. The sustained release profile of siRNA from liposomes ensured prolonged efficacy, contrasting sharply with the transient effects of nonencapsulated siRNA. Mechanistically, silencing of the TRPA1 gene led to decreased microglial activation and reduced expression of inflammatory markers such as ICAM-1 and iba1, mitigating neuroinflammatory responses in the dorsal root ganglia and spinal cord. Intravenous delivery notably outperformed intrathecal administration in downregulating TRPA1 and IL-6 expressions. Overall findings highlight the potential of this nanoengineered TRPA1 siRNA formulation to effectively modulate critical inflammatory pathways and manage CINP. This innovative and exciting strategy not only overcomes the limitations of conventional therapies but also paves the way for new approaches in chronic pain management with significant implications for future clinical applications.