Nanomedicine against oxaliplatin-induced peripheral neuropathy: hypotheses and research perspectives on ion channels and immune microenvironment

Oxaliplatin serves as a cornerstone chemotherapeutic agent for solid tumors (e.g., colorectal and gastric cancers); however, its associated dose-limiting peripheral neuropathy (OIPN) severely compromises patients’ quality of life and treatment completion rates. OIPN manifests as acute cold-induced paresthesia and chronic cumulative sensory neuropathy, with complex, incompletely elucidated pathophysiological mechanisms. This review systematically summarizes the core molecular mechanisms of OIPN, focusing on: (1) sensitization of transient receptor potential vanilloid/ankyrin channels (TRPV1/TRPA1), (2) dysregulated expression and function of voltage-gated sodium channels (NaV1.7, NaV1.8), and (3) the critical role of p38 mitogen-activated protein kinase (p38-MAPK) pathway activation in neuronal hyperexcitability and pain signal transduction within dorsal root ganglion (DRG) sensory neurons. Additionally, we delve into dynamic alterations of the DRG immune microenvironment (notably macrophages and T cells) during OIPN initiation/progression, as well as their crosstalk with neurons. To address the clinical dilemma of limited effective preventive/therapeutic approaches, this review outlines limitations of current strategies and highlights the advantages of nanotechnology-based drug delivery systems in enhancing neuroprotective agent bioavailability and enabling targeted delivery. Finally, we hypothesize the integration of salidroside (a natural product with anti-inflammatory/antioxidant properties) with nanotechnology, and propose leveraging cutting-edge tools (spatial transcriptomics, single-cell RNA sequencing) to elucidate its potential mechanistic action in OIPN—providing a theoretical hypothesis and exploratory research directions for precision OIPN prevention and treatment, in the absence of any empirical evidence for salidroside’s efficacy in this specific pathological context.