Cationic Nanoparticles Mitigate Chemotherapy‐Induced Peripheral Neuropathy

Chemotherapy‐induced peripheral neuropathy (CIPN) is a major clinical challenge, particularly for patients treated with paclitaxel (PTX), a highly effective yet neurotoxic chemotherapeutic agent. PTX often causes debilitating neuropathic pain, including mechanical and cold allodynia, driven by neuroinflammation and altered peripheral neuron excitability. This study investigates PTX‐loaded cationic PAMAM‐Chol nanoparticles (PTX NPs) as a novel strategy to mitigate CIPN. PTX NPs exhibit high drug loading efficiency (99%), sustained release, and reduced neurotoxicity in neuronal cell models. In a murine CIPN model, PTX NPs produce an 85% overall reduction in cold allodynia with a peak inhibition of 90% at day 8 and accelerate the recovery of mechanical allodynia, restoring withdrawal thresholds to baseline levels by day 14, compared to persistent nociception with unencapsulated PTX. PTX NPs also suppress dorsal root ganglia inflammation, reducing the expression of proinflammatory cytokines TNFα and IL‐1β. Furthermore, as indicated by phosphorylated ERK, neuronal activation is prevented in PTX NP‐treated mice, suggesting a reduction in central sensitization. Importantly, PTX NPs demonstrate no observable toxicity in liver or kidney function. These findings establish a proof of concept that nanomedicine‐mediated delivery can alleviate CIPN effectively, offering a promising approach to refine PTX‐based chemotherapy regimens.