Co‑assembled nanoparticles for treatment of chronic musculoskeletal pain by reprogramming neuro‑immune crosstalk and redox homeostasis

Pain is recognized as the fifth vital sign due to its high prevalence and profound impact on quality of life. Recent studies have shown that neuroimmune regulation plays an important role in the development of chronic pain. Tong-Luo-Qu-Tong Ointment (TLQT-O) is a traditional Chinese formulation wildly used for chronic pain. We found that five phytochemicals from TLQT‑O including ferulic acid, safflomin A, kaempferol, cinnamaldehyde and piperine can spontaneously co‑assemble via hydrogen bonds and π-π stacking to form carrier-free spherical nanoparticles (TLQT NPs, abbreviated as TLQT). In a rat knee osteoarthritis model, TLQT reduced pain in von Frey and hot‑plate tests and reduced pain‑related marker levels in dorsal root ganglia. To elucidate underlying mechanisms, we combined network pharmacology with transcriptomic and metabolomic profiling and identified key molecular targets and pathways. TLQT NPs modulated neuro‑immune interactions by influencing the TRPV1-STING-NF‑κB axis. They promoted NRF2 phosphorylation and nuclear translocation while suppressing NF‑κB activation, thereby preserving redox balance. In conclusion, the use of TLQT NPs, as a novel and effective nanotherapeutic strategy, is expected to provide new ideas and methods for the clinical treatment of chronic musculoskeletal pain.