Nanoformulated oxaliplatin reduces platinum accumulation in dermal fibroblasts to alleviate cold allodynia

Oxaliplatin (OXA) is a third-generation platinum-based chemotherapeutic drug for cancer therapy. However, OXA frequently induces peripheral neuropathy, especially cold allodynia, while the underlying mechanisms remain elusive. Herein, we notice that liposomal OXA (Lip-OXA) alleviates cold allodynia in mice compared with free OXA, despite comparable platinum accumulation levels in neural tissues in these two groups, suggesting indirect pathways stimulate peripheral nerves during the OXA therapy. Further investigation indicates that platinum accumulation in dermal extracellular matrix-associated fibroblasts activates the nuclear factor κB (NF-κB) pathway, followed by activation of the chemokine (C-C motif) ligand 2 (CCL2)/C-C motif chemokine receptor 2 (CCR2)/transforming receptor potential cation channel subfamily M member 8 (TRPM8) axis to induce cold allodynia. Nanoformulated OXA treatment reduces cold allodynia due to lower platinum accumulation in the dermis (than that of free OXA). Notably, Lip-OXA shows a superior antitumor efficacy over free OXA in an in situ colorectal cancer model. These findings expand the mechanisms underlying OXA-induced cold allodynia and suggest that nanoformulated OXA can effectively alleviate chemotherapy-induced peripheral neuropathy, while enhancing therapeutic efficacy.